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Mondal T, Chattopadhyay D, Saha Mondal P, Das S, Mondal A, Das A, Samanta S, Saha T. Fusobacterium nucleatum modulates the Wnt/β-catenin pathway in colorectal cancer development. Int J Biol Macromol 2025; 299:140196. [PMID: 39848378 DOI: 10.1016/j.ijbiomac.2025.140196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 01/18/2025] [Accepted: 01/20/2025] [Indexed: 01/25/2025]
Abstract
The Wnt/β-catenin signalling pathway normally maintains cellular and tissue homeostasis by regulating cellular differentiation and survival in a controlled manner. An aberrantly regulated Wnt/β-catenin signalling pathway can transform into an oncogenic pathway, which is associated with Colorectal cancer (CRC) as well as other cancers. CRC is one of the most frequently occurring gastrointestinal cancers worldwide. In CRC tissues, deregulation of Wnt/β-catenin pathway is observed, which indicates that this oncogenic pathway directly promotes CRC malignancy, cell migration, angiogenesis, chemoresistance, as well as shorter lifespan of a patient. Growing evidence suggests that human commensal microbes have a strong association with carcinogenesis, particularly the prevalence and high enrichment of Fusobacterium nucleatum in CRC progression. The Wnt/β-catenin pathway is one of the targeted pathways by F. nucleatum in CRC, where Fusobacterium adhesin attaches to E-cadherin to initiate infection. Also, Wnt/β-catenin pathway can be a potential target for the treatment of both CRC and F. nucleatum-positive CRC. Here, we discuss the underlying mechanisms of F. nucleatum-positive CRC development through modulation of Wnt/β-catenin signalling and its possibility for the application in targeted therapy of F. nucleatum-positive CRC.
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Affiliation(s)
- Tanushree Mondal
- Department of Molecular Biology and Biotechnology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India
| | - Deepanjan Chattopadhyay
- Department of Molecular Biology and Biotechnology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India
| | - Paromita Saha Mondal
- Department of Molecular Biology and Biotechnology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India
| | - Sanjib Das
- Department of Molecular Biology and Biotechnology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India
| | - Amalesh Mondal
- Department of Molecular Biology and Biotechnology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India; Department of Physiology, Katwa Collage, Katwa, Purba Bardhaman, West Bengal 713130, India
| | - Abhishek Das
- Department of Molecular Biology and Biotechnology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India
| | - Subhasree Samanta
- Department of Molecular Biology and Biotechnology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India
| | - Tanima Saha
- Department of Molecular Biology and Biotechnology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India.
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2
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Bagger SM, Schihada H, Walser ALS, Drzazga AK, Grätz L, Palmisano T, Kuhn CK, Mavri M, Mølleskov-Jensen AS, Tall GG, Schöneberg T, Mathiasen SJ, Javitch JA, Schulte G, Spiess K, Rosenkilde MM. Complex G-protein signaling of the adhesion GPCR, ADGRA3. J Biol Chem 2025; 301:108441. [PMID: 40127866 PMCID: PMC12059339 DOI: 10.1016/j.jbc.2025.108441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Accepted: 03/19/2025] [Indexed: 03/26/2025] Open
Abstract
ADGRA3 (GPR125) is an orphan adhesion G protein-coupled receptor (aGPCR) involved in planar cell polarity, primarily through recruitment of the signaling components disheveled (DVL) during vertebrate gastrulation and discs large homolog 1, implicated in cancer. Limited knowledge exists of the canonical G protein-coupled receptor pathways downstream of ADGRA3. Here, we employed a series of human cell line-based signaling assays to gain insight into the G protein-mediated signaling of ADGRA3. We designed ADGRA3 constructs based on transcript variant analysis in publicly available human liver and brain RNA-seq datasets. Cleavage in the GPCR autoproteolysis site (GPS) is an aGPCR hallmark; thus, we generated a truncated ADGRA3 (C-terminal fragment, CTF) corresponding to a potential cleavage at the GPS. We found low-level activation of Gi and Gs by ADGRA3 and slightly more by its CTF. As the N terminus of the CTF constitutes a class-defined tethered agonist (so-called stachel peptide), we removed the initial three amino acids of the CTF. This resulted in abrogated G protein-mediated signaling, as observed for other aGPCRs. Due to the central role of ADGRA3 in planar cell polarity signaling through DVL recruitment, we investigated the G-protein signaling in the absence of DVL1-3 and found it sustained. No transcriptional activation was observed in an assay of downstream β-catenin activity. Collectively, this establishes classical G protein-mediated signaling for ADGRA3.
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Affiliation(s)
- Sofie M Bagger
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hannes Schihada
- Department of Physiology and Pharmacology, Section of Receptor Biology and Signaling, Karolinska Institutet, Stockholm, Sweden
| | - Anna L S Walser
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anna K Drzazga
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lukas Grätz
- Department of Physiology and Pharmacology, Section of Receptor Biology and Signaling, Karolinska Institutet, Stockholm, Sweden
| | - Tiago Palmisano
- Departments of Psychiatry and Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA
| | - Christina K Kuhn
- Molecular Biochemistry, Medical Faculty, Rudolf Schönheimer Institute of Biochemistry, Leipzig, Germany
| | - Maša Mavri
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ann-Sophie Mølleskov-Jensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Gregory G Tall
- Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Torsten Schöneberg
- Molecular Biochemistry, Medical Faculty, Rudolf Schönheimer Institute of Biochemistry, Leipzig, Germany
| | - Signe J Mathiasen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Departments of Psychiatry and Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA
| | - Jonathan A Javitch
- Departments of Psychiatry and Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA
| | - Gunnar Schulte
- Department of Physiology and Pharmacology, Section of Receptor Biology and Signaling, Karolinska Institutet, Stockholm, Sweden
| | - Katja Spiess
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Liu S, Gunzler DD, Gunzler SA, Crawford DC, Briggs FBS. Exploring the early drivers of pain in Parkinson's disease. Sci Rep 2025; 15:6212. [PMID: 39979466 PMCID: PMC11842595 DOI: 10.1038/s41598-025-90678-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 02/14/2025] [Indexed: 02/22/2025] Open
Abstract
Pain is a common and complex non-motor symptom in people with Parkinson's disease (PWP). Little is known about the genetic drivers of pain in PWP, and progress in its study has been challenging. Here, we conducted two genome-wide association studies (GWAS) to identify genetic variants associated with pain experienced during the earliest stages of Parkinson's disease. The study population consisted of 4,159 PWP of European ancestry who were mapped to five previously-described, longitudinal pain trajectories. In the first GWAS, the extreme pain trajectories (highest burden versus no significant pain over time) were compared, and in the second GWAS, a multinomial approach was undertaken. While no variant reached genome-wide significance, we identified promising associations, such as rs117108018 (ORGWAS-Extreme=8.96, pGWAS-Extreme=2.5 × 10- 7), a brain/nerve eQTL for L3MBTL3 and EPB41L2, and rs61881484 (pGWAS-Multinomial=2 × 10- 7), which intersects a transcription factor peak targeting CREB1, critical in sensory neuron synaptic plasticity and neuropathic pain regulation. Gene-based tests implicated CTNNB1 (pGWAS-Extreme=3.2 × 10- 5), KLK7 (pGWAS-Extreme=7 × 10- 5), and SLITRK3 (pGWAS-Multinomial=3.2 × 10- 5), which have been associated with neurodevelopment. At the pathway-level, there was an enrichment for genes involved in neurotransmitter regulation and opioid dependence. This study implicates neuropathic pain mechanisms as prominent drivers of elevated pain in PWP, suggests potential therapeutic genetic targets for further research.
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Affiliation(s)
- Shiying Liu
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Douglas D Gunzler
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Center for Health Care Research and Policy, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Steven A Gunzler
- Neurological Institute, University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Dana C Crawford
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Farren B S Briggs
- Department of Public Health Sciences, University of Miami Miller School of Medicine, FL, Miami, USA.
- Don Soffer Clinical Research Center, 1120 NW 14th St, 922, FL, 33136-2107, Miami, USA.
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Nayak A, Streiff H, Gonzalez I, Adekoya OO, Silva I, Shenoy AK. Wnt Pathway-Targeted Therapy in Gastrointestinal Cancers: Integrating Benchside Insights with Bedside Applications. Cells 2025; 14:178. [PMID: 39936971 PMCID: PMC11816596 DOI: 10.3390/cells14030178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/05/2025] [Accepted: 01/07/2025] [Indexed: 02/13/2025] Open
Abstract
The Wnt signaling pathway is critical in the onset and progression of gastrointestinal (GI) cancers. Anomalies in this pathway, often stemming from mutations in critical components such as adenomatous polyposis coli (APC) or β-catenin, lead to uncontrolled cell proliferation and survival. In the case of colorectal cancer, dysregulation of the Wnt pathway drives tumor initiation and growth. Similarly, aberrant Wnt signaling contributes to tumor development, metastasis, and resistance to therapy in other GI cancers, such as gastric, pancreatic, and hepatocellular carcinomas. Targeting the Wnt pathway or its downstream effectors has emerged as a promising therapeutic strategy for combating these highly aggressive GI malignancies. Here, we review the dysregulation of the Wnt signaling pathway in the pathogenesis of GI cancers and further explore the therapeutic potential of targeting the various components of the Wnt pathway. Furthermore, we summarize and integrate the preclinical evidence supporting the therapeutic efficacy of potent Wnt pathway inhibitors with completed and ongoing clinical trials in GI cancers. Additionally, we discuss the challenges of Wnt pathway-targeted therapies in GI cancers to overcome these concerns for effective clinical translation.
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5
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Menon NA, Kumar CD, Ramachandran P, Blaize B, Gautam M, Cordani M, Lekha Dinesh Kumar. Small-molecule inhibitors of WNT signalling in cancer therapy and their links to autophagy and apoptosis. Eur J Pharmacol 2025; 986:177137. [PMID: 39551337 DOI: 10.1016/j.ejphar.2024.177137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
Cancer represents an intricate and heterogeneous ailment that evolves from a multitude of epigenetic and genetic variations that disrupt normal cellular function. The WNT/β-catenin pathway is essential in maintaining the balance between cell renewal and differentiation in various tissues. Abnormal activation of this pathway can lead to uncontrolled cell growth and initiate cancer across a variety of tissues such as the colon, skin, liver, and ovary. It enhances characteristics that lead to cancer progression, including angiogenesis, invasion and metastasis. Processes like autophagy and apoptosis which regulate cell death and play a crucial role in maintaining cellular equilibrium are also intimately linked with WNT/ β-catenin pathway. Thus, targeting WNT pathway has become a key strategy in developing antitumor therapies. Employing small molecule inhibitors has emerged as a targeted therapy to improve the clinical outcome compared to conventional cancer treatments. Many strategies using small molecule inhibitors for modulating the WNT/β-catenin pathway, such as hindering WNT ligands' secretion or interaction, disrupting receptor complex, and blocking the nuclear translocation of β-catenin have been investigated. These interventions have shown promise in both preclinical and clinical settings. This review provides a comprehensive understanding of the role of WNT/β-catenin signalling pathway's role in cancer, emphasizing its regulation of autophagy and apoptosis. Our goal is to highlight the potential of specific small molecule inhibitors targeting this pathway, fostering the development of novel, tailored cancer treatments.
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Affiliation(s)
- Nayana A Menon
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Chethana D Kumar
- Department of Surgical ICU, Christian Medical College, IDA Scudder Road, Vellore, 632004, Tamil Nadu, India
| | - Pournami Ramachandran
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Britny Blaize
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Mridul Gautam
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain.
| | - Lekha Dinesh Kumar
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India.
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Lateef OM, Foote C, Power G, Manrique-Acevedo C, Padilla J, Martinez-Lemus LA. LIM kinases in cardiovascular health and disease. Front Physiol 2024; 15:1506356. [PMID: 39744707 PMCID: PMC11688343 DOI: 10.3389/fphys.2024.1506356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/28/2024] [Indexed: 01/14/2025] Open
Abstract
The Lim Kinase (LIMK) family of serine/threonine kinases is comprised of LIMK1 and LIMK2, which are central regulators of cytoskeletal dynamics via their well-characterized roles in promoting actin polymerization and destabilizing the cellular microtubular network. The LIMKs have been demonstrated to modulate several fundamental physiological processes, including cell cycle progression, cell motility and migration, and cell differentiation. These processes play important roles in maintaining cardiovascular health. However, LIMK activity in healthy and pathological states of the cardiovascular system is poorly characterized. This review highlights the cellular and molecular mechanisms involved in LIMK activation and inactivation, examining its roles in the pathophysiology of vascular and cardiac diseases such as hypertension, aneurysm, atrial fibrillation, and valvular heart disease. It addresses the LIMKs' involvement in processes that support cardiovascular health, including vasculogenesis, angiogenesis, and endothelial mechanotransduction. The review also features how LIMK activity participates in endothelial cell, vascular smooth muscle cell, and cardiomyocyte physiology and its implications in pathological states. A few recent preclinical studies demonstrate the therapeutic potential of LIMK inhibition. We conclude by proposing that future research should focus on the potential clinical relevance of LIMK inhibitors as therapeutic agents to reduce the burden of cardiovascular disease and improve patient outcomes.
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Affiliation(s)
- Olubodun M. Lateef
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
- Department of Medical Pharmacology and Physiology, University of Missouri Columbia, Columbia, MO, United States
| | - Christopher Foote
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
| | - Gavin Power
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Camila Manrique-Acevedo
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, United States
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Columbia, MO, United States
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, MO, United States
| | - Jaume Padilla
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, United States
| | - Luis A. Martinez-Lemus
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
- Department of Medical Pharmacology and Physiology, University of Missouri Columbia, Columbia, MO, United States
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, MO, United States
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7
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Levy I, Arvidson R. Cephalic ganglia transcriptomics of the American cockroach Periplaneta americana (Blattodea: Blattidae). JOURNAL OF INSECT SCIENCE (ONLINE) 2024; 24:12. [PMID: 39688382 DOI: 10.1093/jisesa/ieae113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/19/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024]
Abstract
The American cockroach Periplaneta americana (L.) (Blattodea, Blattidae) has been a model organism for biochemical and physiological study for almost a century, however, its use does not benefit from the genetic tools found in key model species such as Drosophila melanogaster. To facilitate the use of the cockroach as a model system in neuroscience and to serve as a foundation for functional and translational experimentation, a transcriptome of the cephalic ganglia was assembled and annotated, and differential expression profiles between these ganglia were assessed. The transcriptome assembly yielded >400 k transcripts, with >40 k putative coding sequences. Gene ontology and protein domain searches indicate the cerebral and gnathal ganglia (GNG) have distinct genetic expression profiles. The developmental Toll signaling pathway appears to be active in the adult central nervous system (CNS), which may suggest a separate role for this pathway besides innate immune activation or embryonic development. The catabolic glycolytic and citric acid cycle enzymes are well represented in both ganglia, but key enzymes are more highly expressed in the GNG. Both ganglia express gluconeogenic and trehaloneogenic enzymes, suggesting a larger role of the CNS in regulating hemolymph sugar homeostasis than previously appreciated. The annotation and quantification of the cephalic ganglia transcriptome reveal both canonical and novel pathways in signaling and metabolism in an adult insect and lay a foundation for future functional and genetic analysis.
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Affiliation(s)
- Ilana Levy
- Undergraduate Program in Biochemistry, Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA
| | - Ryan Arvidson
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA
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8
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Tomuleasa C, Tigu AB, Munteanu R, Moldovan CS, Kegyes D, Onaciu A, Gulei D, Ghiaur G, Einsele H, Croce CM. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduct Target Ther 2024; 9:201. [PMID: 39138146 PMCID: PMC11323831 DOI: 10.1038/s41392-024-01899-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/29/2024] [Accepted: 06/14/2024] [Indexed: 08/15/2024] Open
Abstract
Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.
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Affiliation(s)
- Ciprian Tomuleasa
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj Napoca, Romania.
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania.
| | - Adrian-Bogdan Tigu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Raluca Munteanu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Cristian-Silviu Moldovan
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - David Kegyes
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Anca Onaciu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Gulei
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Gabriel Ghiaur
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Department of Leukemia, Sidney Kimmel Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hermann Einsele
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Universitätsklinikum Würzburg, Medizinische Klinik II, Würzburg, Germany
| | - Carlo M Croce
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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Shi DL. Canonical and Non-Canonical Wnt Signaling Generates Molecular and Cellular Asymmetries to Establish Embryonic Axes. J Dev Biol 2024; 12:20. [PMID: 39189260 PMCID: PMC11348223 DOI: 10.3390/jdb12030020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/08/2024] [Accepted: 07/31/2024] [Indexed: 08/28/2024] Open
Abstract
The formation of embryonic axes is a critical step during animal development, which contributes to establishing the basic body plan in each particular organism. Wnt signaling pathways play pivotal roles in this fundamental process. Canonical Wnt signaling that is dependent on β-catenin regulates the patterning of dorsoventral, anteroposterior, and left-right axes. Non-canonical Wnt signaling that is independent of β-catenin modulates cytoskeletal organization to coordinate cell polarity changes and asymmetric cell movements. It is now well documented that components of these Wnt pathways biochemically and functionally interact to mediate cell-cell communications and instruct cellular polarization in breaking the embryonic symmetry. The dysfunction of Wnt signaling disrupts embryonic axis specification and proper tissue morphogenesis, and mutations of Wnt pathway genes are associated with birth defects in humans. This review discusses the regulatory roles of Wnt pathway components in embryonic axis formation by focusing on vertebrate models. It highlights current progress in decoding conserved mechanisms underlying the establishment of asymmetry along the three primary body axes. By providing an in-depth analysis of canonical and non-canonical pathways in regulating cell fates and cellular behaviors, this work offers insights into the intricate processes that contribute to setting up the basic body plan in vertebrate embryos.
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Affiliation(s)
- De-Li Shi
- Department of Medical Research, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China;
- Laboratory of Developmental Biology, Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Sorbonne University, 75005 Paris, France
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10
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Ahmad S, Attisano L. Wnt5a Promotes Axon Elongation in Coordination with the Wnt-Planar Cell Polarity Pathway. Cells 2024; 13:1268. [PMID: 39120298 PMCID: PMC11312420 DOI: 10.3390/cells13151268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/10/2024] Open
Abstract
The establishment of neuronal polarity, involving axon specification and outgrowth, is critical to achieve the proper morphology of neurons, which is important for neuronal connectivity and cognitive functions. Extracellular factors, such as Wnts, modulate diverse aspects of neuronal morphology. In particular, non-canonical Wnt5a exhibits differential effects on neurite outgrowth depending upon the context. Thus, the role of Wnt5a in axon outgrowth and neuronal polarization is not completely understood. In this study, we demonstrate that Wnt5a, but not Wnt3a, promotes axon outgrowth in dissociated mouse embryonic cortical neurons and does so in coordination with the core PCP components, Prickle and Vangl. Unexpectedly, exogenous Wnt5a-induced axon outgrowth was dependent on endogenous, neuronal Wnts, as the chemical inhibition of Porcupine using the IWP2- and siRNA-mediated knockdown of either Porcupine or Wntless inhibited Wnt5a-induced elongation. Importantly, delayed treatment with IWP2 did not block Wnt5a-induced elongation, suggesting that endogenous Wnts and Wnt5a act during specific timeframes of neuronal polarization. Wnt5a in fibroblast-conditioned media can associate with small extracellular vesicles (sEVs), and we also show that these Wnt5a-containing sEVs are primarily responsible for inducing axon elongation.
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Affiliation(s)
| | - Liliana Attisano
- Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada;
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de Pellegars-Malhortie A, Picque Lasorsa L, Mazard T, Granier F, Prévostel C. Why Is Wnt/β-Catenin Not Yet Targeted in Routine Cancer Care? Pharmaceuticals (Basel) 2024; 17:949. [PMID: 39065798 PMCID: PMC11279613 DOI: 10.3390/ph17070949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/04/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Despite significant progress in cancer prevention, screening, and treatment, the still limited number of therapeutic options is an obstacle towards increasing the cancer cure rate. In recent years, many efforts were put forth to develop therapeutics that selectively target different components of the oncogenic Wnt/β-catenin signaling pathway. These include small molecule inhibitors, antibodies, and more recently, gene-based approaches. Although some of them showed promising outcomes in clinical trials, the Wnt/β-catenin pathway is still not targeted in routine clinical practice for cancer management. As for most anticancer treatments, a critical limitation to the use of Wnt/β-catenin inhibitors is their therapeutic index, i.e., the difficulty of combining effective anticancer activity with acceptable toxicity. Protecting healthy tissues from the effects of Wnt/β-catenin inhibitors is a major issue due to the vital role of the Wnt/β-catenin signaling pathway in adult tissue homeostasis and regeneration. In this review, we provide an up-to-date summary of clinical trials on Wnt/β-catenin pathway inhibitors, examine their anti-tumor activity and associated adverse events, and explore strategies under development to improve the benefit/risk profile of this therapeutic approach.
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Affiliation(s)
- Auriane de Pellegars-Malhortie
- IRCM (Montpellier Cancer Research Institute), University of Montpellier, Inserm, ICM (Montpellier Regional Cancer Institute), 34298 Montpellier, CEDEX 5, France; (A.d.P.-M.); (L.P.L.); (T.M.)
| | - Laurence Picque Lasorsa
- IRCM (Montpellier Cancer Research Institute), University of Montpellier, Inserm, ICM (Montpellier Regional Cancer Institute), 34298 Montpellier, CEDEX 5, France; (A.d.P.-M.); (L.P.L.); (T.M.)
| | - Thibault Mazard
- IRCM (Montpellier Cancer Research Institute), University of Montpellier, Inserm, ICM (Montpellier Regional Cancer Institute), 34298 Montpellier, CEDEX 5, France; (A.d.P.-M.); (L.P.L.); (T.M.)
- Medical Oncology Department, ICM, University of Montpellier, CEDEX 5, 34298 Montpellier, France
| | | | - Corinne Prévostel
- IRCM (Montpellier Cancer Research Institute), University of Montpellier, Inserm, ICM (Montpellier Regional Cancer Institute), 34298 Montpellier, CEDEX 5, France; (A.d.P.-M.); (L.P.L.); (T.M.)
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12
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Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y, Dong Q, Wei X. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J Hematol Oncol 2024; 17:46. [PMID: 38886806 PMCID: PMC11184729 DOI: 10.1186/s13045-024-01563-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/31/2024] [Indexed: 06/20/2024] Open
Abstract
The Wnt/β-catenin signaling pathway plays a crucial role in various physiological processes, encompassing development, tissue homeostasis, and cell proliferation. Under normal physiological conditions, the Wnt/β-catenin signaling pathway is meticulously regulated. However, aberrant activation of this pathway and downstream target genes can occur due to mutations in key components of the Wnt/β-catenin pathway, epigenetic modifications, and crosstalk with other signaling pathways. Consequently, these dysregulations contribute significantly to tumor initiation and progression. Therapies targeting the Wnt/β-catenin signaling transduction have exhibited promising prospects and potential for tumor treatment. An increasing number of medications targeting this pathway are continuously being developed and validated. This comprehensive review aims to summarize the latest advances in our understanding of the role played by the Wnt/β-catenin signaling pathway in carcinogenesis and targeted therapy, providing valuable insights into acknowledging current opportunities and challenges associated with targeting this signaling pathway in cancer research and treatment.
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Affiliation(s)
- Pan Song
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Zirui Gao
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yige Bao
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Li Chen
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuhe Huang
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yanyan Liu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Qiang Dong
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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Tophkhane SS, Fu K, Verheyen EM, Richman JM. Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome. Dis Model Mech 2024; 17:dmm050584. [PMID: 38967226 PMCID: PMC11247504 DOI: 10.1242/dmm.050584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 05/16/2024] [Indexed: 07/06/2024] Open
Abstract
Robinow syndrome is a rare disease caused by variants of seven WNT pathway genes. Craniofacial features include widening of the nasal bridge and jaw hypoplasia. We used the chicken embryo to test whether two missense human FZD2 variants (1301G>T, p.Gly434Val; 425C>T, p.Pro142Lys) were sufficient to change frontonasal mass development. In vivo, the overexpression of retroviruses with wild-type or variant human FZD2 inhibited upper beak ossification. In primary cultures, wild-type and variant human FZD2 significantly inhibited chondrogenesis, with the 425C>T variant significantly decreasing activity of a SOX9 luciferase reporter compared to that for the wild type or 1301G>T. Both variants also increased nuclear shuttling of β-catenin (CTNNB1) and increased the expression of TWIST1, which are inhibitory to chondrogenesis. In canonical WNT luciferase assays using frontonasal mass cells, the variants had dominant-negative effects on wild-type FZD2. In non-canonical assays, the 425C>T variant failed to activate the reporter above control levels and was unresponsive to exogenous WNT5A. This is the first single amino acid change to selectively alter ligand binding in a FZD receptor. Therefore, FZD2 missense variants are pathogenic and could lead to the altered craniofacial morphogenesis seen in Robinow syndrome.
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Affiliation(s)
- Shruti S. Tophkhane
- Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Katherine Fu
- Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Esther M. Verheyen
- Department of Molecular Biology and Biochemistry, Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
| | - Joy M. Richman
- Life Sciences Institute and Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Belenkov YN, Iusupova AO, Slepova OA, Pakhtusov NN, Popova LV, Lishuta AS, Krivova AV, Khabarova NV, Abidaev MY, Privalova EV. WNT Signaling Cascade Proteins and LRP6 in the Formation of Various Types of Coronary Lesions in Patients With Coronary Artery Disease. KARDIOLOGIIA 2024; 64:3-10. [PMID: 38841783 DOI: 10.18087/cardio.2024.5.n2626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 06/07/2024]
Abstract
AIM Assessment of WNT1, WNT3a, and LRP6 concentrations in patients with ischemic heart disease (IHD) and obstructive and non-obstructive coronary artery (CA) disease. MATERIAL AND METHODS This cross-sectional observational study included 50 IHD patients (verified by coronary angiography, CAG), of which 25 (50%) were men, mean age 64.9±8.1 years; 20 patients had non-obstructive CA disease (stenosis <50%), and 30 patients had hemodynamically significant stenosis. Concentrations of WNT1, WNT3a and LRP6 were measured in all patients. RESULTS The concentrations of WNT1 and WNT3a proteins were significantly higher in patients with IHD and obstructive CA disease (p < 0.001), while the concentration of LRP6 was higher in the group with non-obstructive CA disease (p = 0.016). Data analysis of the group with obstructive CA disease showed a moderate correlation between WNT1 and LRP6 (ρ=0.374; p=0.042). Correlation analysis of all groups of patients with CA disease revealed a moderate association between the concentrations of WNT1 and uric acid (ρ=0.416; p=0.007). Regression analysis showed that risk factors for the development of IHD, such as increased body mass index, age, smoking, dyslipidemia, and hypertension, did not significantly influence the type of CA disease in IHD patients. According to ROC analysis, the obstructive form of IHD was predicted by a WNT3a concentration higher than 0.155 ng/ml and a LRP6 concentration lower than 12.94 ng/ml. CONCLUSION IHD patients with non-obstructive CA disease had the greatest increase in LRP6, while patients with obstructive CA disease had significantly higher concentrations of the canonical WNT cascade proteins, WNT1 and WNT3a. According to the ROC analysis, a WNT3a concentration >0.155 ng/ml can serve as a predictor for the presence of hemodynamically significant CA stenosis in IHD patients (sensitivity 96.7%; specificity 70%), whereas a LRP6 concentration >12.94 ng/ml can predict the development of non-obstructive CA disease (sensitivity 76.7%; specificity 65%).
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Affiliation(s)
- Yu N Belenkov
- Sechenov First Moscow State Medical University, Moscow
| | - A O Iusupova
- Sechenov First Moscow State Medical University, Moscow
| | - O A Slepova
- Sechenov First Moscow State Medical University, Moscow
| | - N N Pakhtusov
- Sechenov First Moscow State Medical University, Moscow
| | - L V Popova
- Sechenov First Moscow State Medical University, Moscow
| | - A S Lishuta
- Sechenov First Moscow State Medical University, Moscow
| | - A V Krivova
- Sechenov First Moscow State Medical University, Moscow
| | - N V Khabarova
- Sechenov First Moscow State Medical University, Moscow
| | - M Yu Abidaev
- Sechenov First Moscow State Medical University, Moscow
| | - E V Privalova
- Sechenov First Moscow State Medical University, Moscow
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Kamizaki K, Minami Y, Nishita M. Role of the Ror family receptors in Wnt5a signaling. In Vitro Cell Dev Biol Anim 2024; 60:489-501. [PMID: 38587578 DOI: 10.1007/s11626-024-00885-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 01/30/2024] [Indexed: 04/09/2024]
Abstract
Ror-family receptors, Ror1 and Ror2, are type I transmembrane proteins that possess an extracellular cysteine-rich domain, which is conserved throughout the Frizzled-family receptors and is a binding site for Wnt ligands. Both Ror1 and Ror2 function primarily as receptors or co-receptors for Wnt5a to activate the β-catenin-independent, non-canonical Wnt signaling, thereby regulating cell polarity, migration, proliferation, and differentiation depending on the context. Ror1 and Ror2 are expressed highly in many tissues during embryogenesis but minimally or scarcely in adult tissues, with some exceptions. In contrast, Ror1 and Ror2 are expressed in many types of cancers, and their high expression often contributes to the progression of the disease. Therefore, Ror1 and Ror2 have been proposed as potential targets for the treatment of the malignancies. In this review, we provide an overview of the regulatory mechanisms of Ror1/Ror2 expression and discuss how Wnt5a-Ror1/Ror2 signaling is mediated and regulated by their interacting proteins.
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Affiliation(s)
- Koki Kamizaki
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, 650-0017, Japan
| | - Yasuhiro Minami
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, 650-0017, Japan
| | - Michiru Nishita
- Department of Biochemistry, Fukushima Medical University School of Medicine, 1 Hikariga-Oka, Fukushima, 960-1295, Japan.
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Tai Y, Shang J. Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma. Front Endocrinol (Lausanne) 2024; 14:1260701. [PMID: 38269250 PMCID: PMC10806569 DOI: 10.3389/fendo.2023.1260701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 12/20/2023] [Indexed: 01/26/2024] Open
Abstract
Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/β-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/β-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/β-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/β-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/β-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.
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Affiliation(s)
- Yanghao Tai
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Jiwen Shang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Department of Ambulatory Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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17
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Zhang N, Li Y. Receptor tyrosine kinases: biological functions and anticancer targeted therapy. MedComm (Beijing) 2023; 4:e446. [PMID: 38077251 PMCID: PMC10701465 DOI: 10.1002/mco2.446] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 10/16/2024] Open
Abstract
Receptor tyrosine kinases (RTKs) are a class of protein kinases that play crucial roles in various cellular processes, including cell migration, morphological differentiation, cell growth, and angiogenesis. In humans, 58 RTKs have been identified and categorized into 20 distinct families based on the composition of their extracellular regions. RTKs are primarily activated by specific ligands that bind to their extracellular region. They not only regulate tumor transformation, proliferation, metastasis, drug resistance, and angiogenesis, but also initiate and maintain the self-renewal and cloning ability of cancer stem cells. Accurate diagnosis and grading of tumors with dysregulated RTKs are essential in clinical practice. There is a growing body of evidence supporting the benefits of RTKs-targeted therapies for cancer patients, and researchers are actively exploring new targets and developing targeted agents. However, further optimization of RTK inhibitors is necessary to effectively target the diverse RTK alterations observed in human cancers. This review provides insights into the classification, structure, activation mechanisms, and expression of RTKs in tumors. It also highlights the research advances in RTKs targeted anticancer therapy and emphasizes their significance in optimizing cancer diagnosis and treatment strategies.
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Affiliation(s)
- Nan Zhang
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
- Department of Medical OncologyChongqing University Cancer HospitalChongqingChina
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18
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Riquelme R, Li L, Gambrill A, Barria A. ROR2 homodimerization is sufficient to activate a neuronal Wnt/calcium signaling pathway. J Biol Chem 2023; 299:105350. [PMID: 37832874 PMCID: PMC10654037 DOI: 10.1016/j.jbc.2023.105350] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 09/06/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
Wnt signaling plays a key role in the mature CNS by regulating trafficking of NMDA-type glutamate receptors and intrinsic properties of neurons. The Wnt receptor ROR2 has been identified as a necessary component of the neuronal Wnt5a/Ca2+ signaling pathway that regulates synaptic and neuronal function. Since ROR2 is considered a pseudokinase, its mechanism for downstream signaling upon ligand binding has been controversial. It has been suggested that its role is to function as a coreceptor of a G-protein-coupled Wnt receptor of the Frizzled family. We show that chemically induced homodimerization of ROR2 is sufficient to recapitulate key signaling events downstream of receptor activation in neurons, including PKC and JNK kinases activation, elevation of somatic and dendritic Ca2+ levels, and increased trafficking of NMDARs to synapses. In addition, we show that homodimerization of ROR2 induces phosphorylation of the receptor on Tyr residues. Point mutations in the conserved but presumed nonfunctional ATP-binding site of the receptor prevent its phosphorylation, as well as downstream signaling. This suggests an active kinase domain. Our results indicate that ROR2 can signal independently of Frizzled receptors to regulate the trafficking of a key synaptic component. Additionally, they suggest that homodimerization can overcome structural conformations that render the tyrosine kinase inactive. A better understanding of ROR2 signaling is crucial for comprehending the regulation of synaptic and neuronal function in normal brain processes in mature animals.
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Affiliation(s)
- Raul Riquelme
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA
| | - Laura Li
- Neuroscience Undergraduate Program, University of Washington, Seattle, Washington, USA
| | - Abigail Gambrill
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA
| | - Andres Barria
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.
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Zhang L, Adu IK, Zhang H, Wang J. The WNT/β-catenin system in chronic kidney disease-mineral bone disorder syndrome. Int Urol Nephrol 2023; 55:2527-2538. [PMID: 36964322 DOI: 10.1007/s11255-023-03569-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 03/18/2023] [Indexed: 03/26/2023]
Abstract
BACKGROUND The WNT/β-catenin system is an evolutionarily conserved signaling pathway that plays a crucial role in morphogenesis and cell tissue formation during embryogenesis. Although usually suppressed in adulthood, it can be reactivated during organ damage and regeneration. Transient activation of the WNT/β-catenin pathway stimulates tissue regeneration after acute kidney injury, while persistent (uncontrolled) activation can promote the development of chronic kidney disease (CKD). CKD-MBD is a clinical syndrome that develops with systemic mineral and bone metabolism disorders caused by CKD, characterized by abnormal bone mineral metabolism and/or extraosseous calcification, as well as cardiovascular disease associated with CKD, including vascular stiffness and calcification. OBJECTIVE This paper aims to comprehensively review the WNT/β-catenin signaling pathway in relation to CKD-MBD, focusing on its components, regulatory molecules, and regulatory mechanisms. Additionally, this review highlights the challenges and opportunities for using small molecular compounds to target the WNT/β-catenin signaling pathway in CKD-MBD therapy. METHODS We conducted a comprehensive literature review using various scientific databases, including PubMed, Scopus, and Web of Science, to identify relevant articles. We searched for articles that discussed the WNT/β-catenin signaling pathway, CKD-MBD, and their relationship. We also reviewed articles that discussed the components of the WNT/β-catenin signaling pathway, its regulatory molecules, and regulatory mechanisms. RESULTS The WNT/β-catenin signaling pathway plays a crucial role in CKD-MBD by promoting vascular calcification and bone mineral metabolism disorders. The pathway's components include WNT ligands, Frizzled receptors, and LRP5/6 co-receptors, which initiate downstream signaling cascades leading to the activation of β-catenin. Several regulatory molecules, including GSK-3β, APC, and Axin, modulate β-catenin activation. The WNT/β-catenin signaling pathway also interacts with other signaling pathways, such as the BMP pathway, to regulate CKD-MBD. CONCLUSIONS The WNT/β-catenin signaling pathway is a potential therapeutic target for CKD-MBD. Small molecular compounds that target the components or regulatory molecules of the pathway may provide a promising approach to treat CKD-MBD. However, more research is needed to identify safe and effective compounds and to determine the optimal dosages and treatment regimens.
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Affiliation(s)
- Lingbo Zhang
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, People's Republic of China
| | - Isaac Kumi Adu
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, People's Republic of China
- Department of Internal Medicine, The Second Hospital of Jingzhou and the Affiliated Hospital of Hubei College of Chinese Medicine, Jingzhou, People's Republic of China
- Department of Internal Medicine, Kings and Queens University College and Teaching Hospital, Akosombo, Ghana
| | - Haifeng Zhang
- Department of Internal Medicine, The Second Hospital of Jingzhou and the Affiliated Hospital of Hubei College of Chinese Medicine, Jingzhou, People's Republic of China
| | - Jiancheng Wang
- Department of Internal Medicine, The Second Hospital of Jingzhou and the Affiliated Hospital of Hubei College of Chinese Medicine, Jingzhou, People's Republic of China.
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20
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Seo HS, Yu D, Popov I, Tao J, Angermeier A, Sha B, Axelrod JD, Chang C, Wang J. Prickle and Ror modulate Dishevelled-Vangl interaction to regulate non-canonical Wnt signaling during convergent extension. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.29.555374. [PMID: 37693429 PMCID: PMC10491138 DOI: 10.1101/2023.08.29.555374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Convergent extension (CE) is a fundamental morphogenetic process where oriented cell behaviors lead to polarized extension of diverse tissues. In vertebrates, regulation of CE requires both non-canonical Wnt, its co-receptor Ror, and "core members" of the planar cell polarity (PCP) pathway. PCP was originally identified as a mechanism to coordinate the cellular polarity in the plane of static epithelium, where core proteins Frizzled (Fz)/ Dishevelled (Dvl) and Van Gogh-like (Vangl)/ Prickel (Pk) partition to opposing cell cortex. But how core PCP proteins interact with each other to mediate non-canonical Wnt/ Ror signaling during CE is not clear. We found previously that during CE, Vangl cell-autonomously recruits Dvl to the plasma membrane but simultaneously keeps Dvl inactive. In this study, we show that non-canonical Wnt induces Dvl to transition from Vangl to Fz. PK inhibits the transition, and functionally synergize with Vangl to suppress Dvl during CE. Conversely, Ror is required for the transition, and functionally antagonizes Vangl. Biochemically, Vangl interacts directly with both Ror and Dvl. Ror and Dvl do not bind directly, but can be cofractionated with Vangl. We propose that Pk assists Vangl to function as an unconventional adaptor that brings Dvl and Ror into a complex to serves two functions: 1) simultaneously preventing both Dvl and Ror from ectopically activating non-canonical Wnt signaling; and 2) relaying Dvl to Fz for signaling activation upon non-canonical Wnt induced dimerization of Fz and Ror.
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Ventura E, Belfiore A, Iozzo RV, Giordano A, Morrione A. Progranulin and EGFR modulate receptor-like tyrosine kinase sorting and stability in mesothelioma cells. Am J Physiol Cell Physiol 2023; 325:C391-C405. [PMID: 37399497 PMCID: PMC10393324 DOI: 10.1152/ajpcell.00248.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/26/2023] [Accepted: 06/26/2023] [Indexed: 07/05/2023]
Abstract
Progranulin is a growth factor with pro-tumorigenic activity. We recently demonstrated that in mesothelioma, progranulin regulates cell migration, invasion, adhesion, and in vivo tumor formation by modulating a complex signaling network involving multiple receptor tyrosine kinase (RTK)s. Progranulin biological activity relies on epidermal growth factor receptor (EGFR) and receptor-like tyrosine kinase (RYK), a co-receptor of the Wnt signaling pathway, which are both required for progranulin-induced downstream signaling. However, the molecular mechanism regulating the functional interaction among progranulin, EGFR, and RYK are not known. In this study, we demonstrated that progranulin directly interacted with RYK by specific enzyme-linked immunosorbent assay (ELISA) (KD = 0.67). Using immunofluorescence and proximity ligation assay, we further discovered that progranulin and RYK colocalized in mesothelioma cells in distinct vesicular compartments. Notably, progranulin-dependent downstream signaling was sensitive to endocytosis inhibitors, suggesting that it could depend on RYK or EGFR internalization. We discovered that progranulin promoted RYK ubiquitination and endocytosis preferentially through caveolin-1-enriched pathways, and modulated RYK stability. Interestingly, we also showed that in mesothelioma cells, RYK complexes with the EGFR, contributing to the regulation of RYK stability. Collectively, our results suggest a complex regulation of RYK trafficking/activity in mesothelioma cells, a process that is concurrently regulated by exogenous soluble progranulin and EGFR. NEW & NOTEWORTHY The growth factor progranulin has pro-tumorigenic activity. In mesothelioma, progranulin signaling is mediated by EGFR and RYK, a co-receptor of the Wnt signaling. However, the molecular mechanisms regulating progranulin action are not well defined. Here, we demonstrated that progranulin binds RYK and regulates its ubiquitination, internalization, and trafficking. We also uncovered a role for EGFR in modulating RYK stability. Overall, these results highlight a complex modulation of RYK activity by progranulin and EGFR in mesothelioma.
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Affiliation(s)
- Elisa Ventura
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States
| | - Antonino Belfiore
- Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Renato V Iozzo
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States
- Department of Biomedical Biotechnologies, University of Siena, Siena, Italy
| | - Andrea Morrione
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States
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Kostes WW, Brafman DA. The Multifaceted Role of WNT Signaling in Alzheimer's Disease Onset and Age-Related Progression. Cells 2023; 12:1204. [PMID: 37190113 PMCID: PMC10136584 DOI: 10.3390/cells12081204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
The evolutionary conserved WNT signaling pathway orchestrates numerous complex biological processes during development and is critical to the maintenance of tissue integrity and homeostasis in the adult. As it relates to the central nervous system, WNT signaling plays several roles as it relates to neurogenesis, synaptic formation, memory, and learning. Thus, dysfunction of this pathway is associated with multiple diseases and disorders, including several neurodegenerative disorders. Alzheimer's disease (AD) is characterized by several pathologies, synaptic dysfunction, and cognitive decline. In this review, we will discuss the various epidemiological, clinical, and animal studies that demonstrate a precise link between aberrant WNT signaling and AD-associated pathologies. In turn, we will discuss the manner in which WNT signaling influences multiple molecular, biochemical, and cellular pathways upstream of these end-point pathologies. Finally, we will discuss how merging tools and technologies can be used to generate next generation cellular models to dissect the relationship between WNT signaling and AD.
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Affiliation(s)
| | - David A. Brafman
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85287, USA
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23
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Kanaoka Y, Onodera K, Watanabe K, Hayashi Y, Usui T, Uemura T, Hattori Y. Inter-organ Wingless/Ror/Akt signaling regulates nutrient-dependent hyperarborization of somatosensory neurons. eLife 2023; 12:79461. [PMID: 36647607 PMCID: PMC9844989 DOI: 10.7554/elife.79461] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 12/11/2022] [Indexed: 01/18/2023] Open
Abstract
Nutrition in early life has profound effects on an organism, altering processes such as organogenesis. However, little is known about how specific nutrients affect neuronal development. Dendrites of class IV dendritic arborization neurons in Drosophila larvae become more complex when the larvae are reared on a low-yeast diet compared to a high-yeast diet. Our systematic search for key nutrients revealed that the neurons increase their dendritic terminal densities in response to a combined deficiency in vitamins, metal ions, and cholesterol. The deficiency of these nutrients upregulates Wingless in a closely located tissue, body wall muscle. Muscle-derived Wingless activates Akt in the neurons through the receptor tyrosine kinase Ror, which promotes the dendrite branching. In larval muscles, the expression of wingless is regulated not only in this key nutrient-dependent manner, but also by the JAK/STAT signaling pathway. Additionally, the low-yeast diet blunts neuronal light responsiveness and light avoidance behavior, which may help larvae optimize their survival strategies under low-nutritional conditions. Together, our studies illustrate how the availability of specific nutrients affects neuronal development through inter-organ signaling.
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Affiliation(s)
| | - Koun Onodera
- Graduate School of Biostudies, Kyoto UniversityKyotoJapan
| | - Kaori Watanabe
- Graduate School of Biostudies, Kyoto UniversityKyotoJapan
| | - Yusaku Hayashi
- Graduate School of Biostudies, Kyoto UniversityKyotoJapan
| | - Tadao Usui
- Graduate School of Biostudies, Kyoto UniversityKyotoJapan
| | - Tadashi Uemura
- Graduate School of Biostudies, Kyoto UniversityKyotoJapan
- Research Center for Dynamic Living Systems, Kyoto UniversityKyotoJapan
- AMED-CRESTTokyoJapan
| | - Yukako Hattori
- Graduate School of Biostudies, Kyoto UniversityKyotoJapan
- JST FORESTTokyoJapan
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24
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Sutton NR, Malhotra R, Hilaire C, Aikawa E, Blumenthal RS, Gackenbach G, Goyal P, Johnson A, Nigwekar SU, Shanahan CM, Towler DA, Wolford BN, Chen Y. Molecular Mechanisms of Vascular Health: Insights From Vascular Aging and Calcification. Arterioscler Thromb Vasc Biol 2023; 43:15-29. [PMID: 36412195 PMCID: PMC9793888 DOI: 10.1161/atvbaha.122.317332] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/11/2022] [Indexed: 11/23/2022]
Abstract
Cardiovascular disease is the most common cause of death worldwide, especially beyond the age of 65 years, with the vast majority of morbidity and mortality due to myocardial infarction and stroke. Vascular pathology stems from a combination of genetic risk, environmental factors, and the biologic changes associated with aging. The pathogenesis underlying the development of vascular aging, and vascular calcification with aging, in particular, is still not fully understood. Accumulating data suggests that genetic risk, likely compounded by epigenetic modifications, environmental factors, including diabetes and chronic kidney disease, and the plasticity of vascular smooth muscle cells to acquire an osteogenic phenotype are major determinants of age-associated vascular calcification. Understanding the molecular mechanisms underlying genetic and modifiable risk factors in regulating age-associated vascular pathology may inspire strategies to promote healthy vascular aging. This article summarizes current knowledge of concepts and mechanisms of age-associated vascular disease, with an emphasis on vascular calcification.
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Affiliation(s)
- Nadia R. Sutton
- Division of Cardiovascular Medicine, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Rajeev Malhotra
- Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Cynthia Hilaire
- Division of Cardiology, Departments of Medicine and Bioengineering, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, 1744 BSTWR, 200 Lothrop St, Pittsburgh, PA, 15260 USA
| | - Elena Aikawa
- Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
| | - Roger S. Blumenthal
- Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease; Baltimore, MD
| | - Grace Gackenbach
- Division of Cardiovascular Medicine, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Parag Goyal
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Adam Johnson
- Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Sagar U. Nigwekar
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Catherine M. Shanahan
- School of Cardiovascular and Metabolic Medicine and Sciences, King’s College London, London, UK
| | - Dwight A. Towler
- Department of Medicine | Endocrine Division and Pak Center for Mineral Metabolism Research, UT Southwestern Medical Center, Dallas, TX USA
| | - Brooke N. Wolford
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
| | - Yabing Chen
- Department of Pathology, University of Alabama at Birmingham and Research Department, Veterans Affairs Birmingham Medical Center, Birmingham, AL, USA
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25
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Siepe DH, Henneberg LT, Wilson SC, Hess GT, Bassik MC, Zinn K, Garcia KC. Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform. eLife 2022; 11:e81398. [PMID: 36178190 PMCID: PMC9578707 DOI: 10.7554/elife.81398] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 09/29/2022] [Indexed: 11/20/2022] Open
Abstract
Secreted proteins, which include cytokines, hormones, and growth factors, are extracellular ligands that control key signaling pathways mediating cell-cell communication within and between tissues and organs. Many drugs target secreted ligands and their cell surface receptors. Still, there are hundreds of secreted human proteins that either have no identified receptors ('orphans') or are likely to act through cell surface receptors that have not yet been characterized. Discovery of secreted ligand-receptor interactions by high-throughput screening has been problematic, because the most commonly used high-throughput methods for protein-protein interaction (PPI) screening are not optimized for extracellular interactions. Cell-based screening is a promising technology for the deorphanization of ligand-receptor interactions, because multimerized ligands can enrich for cells expressing low affinity cell surface receptors, and such methods do not require purification of receptor extracellular domains. Here, we present a proteo-genomic cell-based CRISPR activation (CRISPRa) enrichment screening platform employing customized pooled cell surface receptor sgRNA libraries in combination with a magnetic bead selection-based enrichment workflow for rapid, parallel ligand-receptor deorphanization. We curated 80 potentially high-value orphan secreted proteins and ultimately screened 20 secreted ligands against two cell sgRNA libraries with targeted expression of all single-pass (TM1) or multi-pass transmembrane (TM2+) receptors by CRISPRa. We identified previously unknown interactions in 12 of these screens, and validated several of them using surface plasmon resonance and/or cell binding assays. The newly deorphanized ligands include three receptor protein tyrosine phosphatase (RPTP) ligands and a chemokine-like protein that binds to killer immunoglobulin-like receptors (KIRs). These new interactions provide a resource for future investigations of interactions between the human-secreted and membrane proteomes.
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Affiliation(s)
- Dirk H Siepe
- Department of Molecular and Cellular Physiology, Stanford UniversityStanfordUnited States
| | - Lukas T Henneberg
- Department of Molecular and Cellular Physiology, Stanford UniversityStanfordUnited States
| | - Steven C Wilson
- Department of Molecular and Cellular Physiology, Stanford UniversityStanfordUnited States
| | - Gaelen T Hess
- Stanford ChEM-H, Department of Genetics, Stanford UniversityStanfordUnited States
| | - Michael C Bassik
- Stanford ChEM-H, Department of Genetics, Stanford UniversityStanfordUnited States
| | - Kai Zinn
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
| | - K Christopher Garcia
- Department of Molecular and Cellular Physiology, Stanford UniversityStanfordUnited States
- Howard Hughes Medical Institute, Stanford University School of MedicineStanfordUnited States
- Department of Structural Biology, Stanford University School of MedicineStanfordUnited States
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26
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Masbuchin AN, Widodo, Rohman MS, Liu PY. The two facets of receptor tyrosine kinase in cardiovascular calcification-can tyrosine kinase inhibitors benefit cardiovascular system? Front Cardiovasc Med 2022; 9:986570. [PMID: 36237897 PMCID: PMC9552878 DOI: 10.3389/fcvm.2022.986570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/29/2022] [Indexed: 01/09/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment due to their effectiveness in cancer cell killing. However, an off-target of this agent limits its success. Cardiotoxicity-associated TKIs have been widely reported. Tyrosine kinase is involved in many regulatory processes in a cell, and it is involved in cancer formation. Recent evidence suggests the role of tyrosine kinase in cardiovascular calcification, specifically, the calcification of heart vessels and valves. Herein, we summarized the accumulating evidence of the crucial role of receptor tyrosine kinase (RTK) in cardiovascular calcification and provided the potential clinical implication of TKIs-related ectopic calcification. We found that RTKs, depending on the ligand and tissue, can induce or suppress cardiovascular calcification. Therefore, RTKs may have varying effects on ectopic calcification. Additionally, in the context of cardiovascular calcification, TKIs do not always relate to an unfavored outcome-they might offer benefits in some cases.
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Affiliation(s)
- Ainun Nizar Masbuchin
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Widodo
- Department of Biology, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, Indonesia
| | - Mohammad Saifur Rohman
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Ping-Yen Liu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Division of Cardiology, Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Sarraf TR, Sen M. Wnt5A signaling supports antigen processing and CD8 T cell activation. Front Immunol 2022; 13:960060. [PMID: 36091060 PMCID: PMC9459031 DOI: 10.3389/fimmu.2022.960060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
Antigen processing and antigen-specific CD8 T cell activation form part and parcel of cell-mediated immunity to infections. Yet, several lacunae remain in our understanding of how antigen processing and CD8 T cell response are coordinated. In this study, using mouse bone marrow-derived dendritic cells (BMDC) as antigen-presenting cells and Ovalbumin (OVA)/DQ-Ovalbumin (DQ-OVA) as model antigen we demonstrated that Wnt5A signaling in BMDC supports antigen processing/presentation and concomitant CD8 T cell activation through regulation of actin and proteasome dynamics. Recombinant Wnt5A conditioning of BMDC and associated actin assembly facilitated DQ-OVA processing, which was inhibited by the proteasome inhibitor MG132. Moreover, Wnt5A depletion led to a significant reduction in OVA processing and presentation. Impaired DQ-OVA processing in Wnt5A depleted BMDC correlated with altered dynamics of both actin and the proteasome regulator PA28α-PA28β, and reduced association of DQ-OVA with actin and proteasome subunits. Inhibited OVA processing/presentation in the Wnt5A depleted BMDC also resulted in subdued activation of OVA-sensitized CD8 T cells in co-culture with the BMDC. In concurrence with these findings, we demonstrated reduced OVA processing and impaired CD8 T cell response to OVA immunization in Wnt5A heterozygous mice lacking a copy of the Wnt5A gene in comparison to the wild-type cohorts. Taken together, our results reveal a crucial requirement of Wnt5A signaling in antigen processing/presentation and CD8 T cell activation, thus unveiling a vital regulatory node of cell-mediated immunity, unidentified thus far.
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WNT/RYK signaling functions as an antiinflammatory modulator in the lung mesenchyme. Proc Natl Acad Sci U S A 2022; 119:e2201707119. [PMID: 35671428 PMCID: PMC9214544 DOI: 10.1073/pnas.2201707119] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
WNT/β-catenin signaling is critical for lung development, and homeostasis and it has also been implicated in inflammatory lung diseases. However, the underlying molecular mechanisms, especially those at play during inflammatory conditions, are unclear. Here, we show that loss of the WNT coreceptor Related to receptor tyrosine kinase (RYK) specifically in mesenchymal cells results in lung inflammation. Our data indicate that RYK signaling through β-catenin and Nuclear Factor kappa B (NF-κB) is part of a safeguard mechanism against mesenchymal cell death, excessive inflammatory cytokine production, and inflammatory cell recruitment and accumulation. A number of inflammatory lung diseases, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and pneumonia, are modulated by WNT/β-catenin signaling. However, the underlying molecular mechanisms remain unclear. Here, starting with a forward genetic screen in mouse, we identify the WNT coreceptor Related to receptor tyrosine kinase (RYK) acting in mesenchymal tissues as a cell survival and antiinflammatory modulator. Ryk mutant mice exhibit lung hypoplasia and inflammation as well as alveolar simplification due to defective secondary septation, and deletion of Ryk specifically in mesenchymal cells also leads to these phenotypes. By analyzing the transcriptome of wild-type and mutant lungs, we observed the up-regulation of proapoptotic and inflammatory genes whose expression can be repressed by WNT/RYK signaling in vitro. Moreover, mesenchymal Ryk deletion at postnatal and adult stages can also lead to lung inflammation, thus indicating a continued role for WNT/RYK signaling in homeostasis. Our results indicate that RYK signaling through β-catenin and Nuclear Factor kappa B (NF-κB) is part of a safeguard mechanism against mesenchymal cell death, excessive inflammatory cytokine production, and inflammatory cell recruitment and accumulation. Notably, RYK expression is down-regulated in the stromal cells of pneumonitis patient lungs. Altogether, our data reveal that RYK signaling plays critical roles as an antiinflammatory modulator during lung development and homeostasis and provide an animal model to further investigate the etiology of, and therapeutic approaches to, inflammatory lung diseases.
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Min JK, Park HS, Lee YB, Kim JG, Kim JI, Park JB. Cross-Talk between Wnt Signaling and Src Tyrosine Kinase. Biomedicines 2022; 10:biomedicines10051112. [PMID: 35625853 PMCID: PMC9138253 DOI: 10.3390/biomedicines10051112] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/09/2022] [Accepted: 05/09/2022] [Indexed: 12/17/2022] Open
Abstract
Src, a non-receptor tyrosine kinase, was first discovered as a prototype oncogene and has been shown to critical for cancer progression for a variety of tissues. Src activity is regulated by a number of post-translational modifications in response to various stimuli. Phosphorylations of Src Tyr419 (human; 416 in chicken) and Src Tyr530 (human; 527 in chicken) have been known to be critical for activation and inactivation of Src, respectively. Wnt signaling regulates a variety of cellular functions including for development and cell proliferation, and has a role in certain diseases such as cancer. Wnt signaling is carried out through two pathways: β-catenin-dependent canonical and β-catenin-independent non-canonical pathways as Wnt ligands bind to their receptors, Frizzled, LRP5/6, and ROR1/2. In addition, many signaling components including Axin, APC, Damm, Dishevelled, JNK kinase and Rho GTPases contribute to these canonical and non-canonical Wnt pathways. However, the communication between Wnt signaling and Src tyrosine kinase has not been well reviewed as Src regulates Wnt signaling through LRP6 tyrosine phosphorylation. GSK-3β phosphorylated by Wnt also regulates Src activity. As Wnt signaling and Src mutually regulate each other, it is noted that aberrant regulation of these components give rise to various diseases including typically cancer, and as such, merit a closer look.
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Affiliation(s)
- Jung Ki Min
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon 25242, Korea; (J.K.M.); (Y.-B.L.); (J.-G.K.)
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Hwee-Seon Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (H.-S.P.); (J.-I.K.)
- Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Yoon-Beom Lee
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon 25242, Korea; (J.K.M.); (Y.-B.L.); (J.-G.K.)
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Jae-Gyu Kim
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon 25242, Korea; (J.K.M.); (Y.-B.L.); (J.-G.K.)
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (H.-S.P.); (J.-I.K.)
- Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jae-Bong Park
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon 25242, Korea; (J.K.M.); (Y.-B.L.); (J.-G.K.)
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon 24252, Korea
- Correspondence: ; Tel.: +82-33-248-2542; Fax: +82-33-244-8425
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Xiao Q, Werner J, Venkatachalam N, Boonekamp KE, Ebert MP, Zhan T. Cross-Talk between p53 and Wnt Signaling in Cancer. Biomolecules 2022; 12:453. [PMID: 35327645 PMCID: PMC8946298 DOI: 10.3390/biom12030453] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/11/2022] [Accepted: 03/12/2022] [Indexed: 11/16/2022] Open
Abstract
Targeting cancer hallmarks is a cardinal strategy to improve antineoplastic treatment. However, cross-talk between signaling pathways and key oncogenic processes frequently convey resistance to targeted therapies. The p53 and Wnt pathway play vital roles for the biology of many tumors, as they are critically involved in cancer onset and progression. Over recent decades, a high level of interaction between the two pathways has been revealed. Here, we provide a comprehensive overview of molecular interactions between the p53 and Wnt pathway discovered in cancer, including complex feedback loops and reciprocal transactivation. The mutational landscape of genes associated with p53 and Wnt signaling is described, including mutual exclusive and co-occurring genetic alterations. Finally, we summarize the functional consequences of this cross-talk for cancer phenotypes, such as invasiveness, metastasis or drug resistance, and discuss potential strategies to pharmacologically target the p53-Wnt interaction.
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Affiliation(s)
- Qiyun Xiao
- Department of Medicine II, Mannheim University Hospital, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany; (Q.X.); (N.V.); (M.P.E.)
| | - Johannes Werner
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), and Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, D-69120 Heidelberg, Germany; (J.W.); (K.E.B.)
| | - Nachiyappan Venkatachalam
- Department of Medicine II, Mannheim University Hospital, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany; (Q.X.); (N.V.); (M.P.E.)
| | - Kim E. Boonekamp
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), and Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, D-69120 Heidelberg, Germany; (J.W.); (K.E.B.)
| | - Matthias P. Ebert
- Department of Medicine II, Mannheim University Hospital, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany; (Q.X.); (N.V.); (M.P.E.)
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
| | - Tianzuo Zhan
- Department of Medicine II, Mannheim University Hospital, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany; (Q.X.); (N.V.); (M.P.E.)
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
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31
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Rozen EJ, Shohet JM. Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology. Cancer Metastasis Rev 2022; 41:33-52. [PMID: 34716856 PMCID: PMC8924100 DOI: 10.1007/s10555-021-10001-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Neuroblastoma is a devastating disease accounting for 15% of all childhood cancer deaths. Yet, our understanding of key molecular drivers such as receptor tyrosine kinases (RTKs) in this pathology remains poorly clarified. Here, we provide a systematic analysis of the RTK superfamily in the context of neuroblastoma pathogenesis. METHODS Statistical correlations for all RTK family members' expression to neuroblastoma patient survival across 10 independent patient cohorts were annotated, synthesized, and ranked using the R2: Genomics Analysis and Visualization Platform. Gene expression of selected members across different cancer cell lines was further analyzed in the Cancer Cell Line Encyclopedia, part of the Cancer Dependency Map portal (depmap portal ( http://depmap.org )). Finally, we provide a detailed literature review for highly ranked candidates. RESULTS Our analysis defined two subsets of RTKs showing robust associations with either better or worse survival, constituting potential novel players in neuroblastoma pathophysiology, diagnosis, and therapy. We review the available literature regarding the oncogenic functions of these RTKs, their roles in neuroblastoma pathophysiology, and potential utility as therapeutic targets. CONCLUSIONS Our systematic analysis and review of the RTK superfamily in neuroblastoma pathogenesis provides a new resource to guide the research community towards focused efforts investigating signaling pathways that contribute to neuroblastoma tumor establishment, growth, and/or aggressiveness and targeting these druggable molecules in novel therapeutic strategies.
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Affiliation(s)
- Esteban Javier Rozen
- Department of Pediatrics, UMass Chan Medical School, Lazare Research Building LRB603, 364 Plantation Street, Worcester, MA, 01605, USA.
| | - Jason Matthew Shohet
- Division of Hematology/Oncology, Department of Pediatrics, UMass Chan Medical School, Lazare Research Building LRB603, 364 Plantation Street, Worcester, MA, 01605, USA.
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32
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Koushyar S, Meniel VS, Phesse TJ, Pearson HB. Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer. Biomolecules 2022; 12:309. [PMID: 35204808 PMCID: PMC8869457 DOI: 10.3390/biom12020309] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/09/2022] [Accepted: 02/12/2022] [Indexed: 12/24/2022] Open
Abstract
Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence of activating the Wnt pathway during the different stages of prostate cancer progression remains unclear. Preclinical work investigating the efficacy of targeting Wnt signaling for the treatment of prostate cancer, both in primary and metastatic lesions, and improving our molecular understanding of treatment responses is crucial to identifying effective treatment strategies and biomarkers that help guide treatment decisions and improve patient care. In this review, we outline the type of genetic alterations that lead to activated Wnt signaling in prostate cancer, highlight the range of laboratory models used to study the role of Wnt genetic drivers in prostate cancer, and discuss new mechanistic insights into how the Wnt cascade facilitates prostate cancer growth, metastasis, and drug resistance.
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Affiliation(s)
- Sarah Koushyar
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (S.K.); (V.S.M.)
- School of Life Sciences, Pharmacy and Chemistry, Faculty of Science, Engineering and Computing, Kingston University, Penrhyn Road, Kingston Upon Thames KT1 2EE, UK
| | - Valerie S. Meniel
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (S.K.); (V.S.M.)
| | - Toby J. Phesse
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (S.K.); (V.S.M.)
- The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne 3000, Australia
| | - Helen B. Pearson
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (S.K.); (V.S.M.)
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de la Cruz L, Riquelme R, Vivas O, Barria A, Jensen JB. Dishevelled coordinates phosphoinositide kinases PI4KIIIα and PIP5KIγ for efficient PtdInsP2 synthesis. J Cell Sci 2022; 135:274231. [PMID: 34982154 PMCID: PMC8919331 DOI: 10.1242/jcs.259145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 12/14/2021] [Indexed: 02/05/2023] Open
Abstract
Phosphatidylinositol(4,5)-bisphosphate (PtdInsP2) is an important modulator of many cellular processes, and its abundance in the plasma membrane is closely regulated. We examined the hypothesis that members of the Dishevelled scaffolding protein family can bind the lipid kinases phosphatidylinositol 4-kinase (PI4K) and phosphatidylinositol 4-phosphate 5-kinase (PIP5K), facilitating synthesis of PtdInsP2 directly from phosphatidylinositol. We used several assays for PtdInsP2 to examine the cooperative function of phosphoinositide kinases and the Dishevelled protein Dvl3 in the context of two receptor signaling cascades. Simultaneous overexpression of PI4KIIIα (also known as PI4KA) and PIP5KIγ (also known as PIP5K1C) had a synergistic effect on PtdInsP2 synthesis that was recapitulated by overexpression of Dvl3. Increasing the activity of Dvl3 by overexpression increased resting plasma membrane PtdInsP2. Knockdown of Dvl3 reduced resting plasma membrane PtdInsP2 and slowed PtdInsP2 resynthesis following receptor activation. We confirm that Dvl3 promotes coupling of PI4KIIIα and PIP5KIγ and show that this interaction is essential for efficient resynthesis of PtdInsP2 following receptor activation.
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Guo R, Xing QS. Roles of Wnt Signaling Pathway and ROR2 Receptor in Embryonic Development: An Update Review Article. Epigenet Insights 2022; 15:25168657211064232. [PMID: 35128307 PMCID: PMC8808015 DOI: 10.1177/25168657211064232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 11/15/2021] [Indexed: 11/15/2022] Open
Abstract
The Wnt family is a large class of highly conserved cysteine-rich secretory glycoproteins that play a vital role in various cellular and physiological courses through different signaling pathways during embryogenesis and tissue homeostasis 3. Wnt5a is a secreted glycoprotein that belongs to the noncanonical Wnt family and is involved in a wide range of developmental and tissue homeostasis. A growing body of evidence suggests that Wnt5a affects embryonic development, signaling through various receptors, starting with the activation of β-catenin by Wnt5a. In addition to affecting planar cell polarity and Ca2+ pathways, β-catenin also includes multiple signaling cascades that regulate various cell functions. Secondly, Wnt5a can bind to Ror receptors to mediate noncanonical Wnt signaling and a significant ligand for Ror2 in vertebrates. Consistent with the multiple functions of Wnt5A/Ror2 signaling, Wnt5A knockout mice exhibited various phenotypic defects, including an inability to extend the anterior and posterior axes of the embryo. Numerous essential roles of Wnt5a/Ror2 in development have been demonstrated. Therefore, Ror signaling pathway become a necessary target for diagnosing and treating human diseases. The Wnt5a- Ror2 signaling pathway as a critical factor has attracted extensive attention.
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Affiliation(s)
- Rui Guo
- Qingdao University, Qingdao, China
| | - Quan Sheng Xing
- Qingdao University-Affiliated Hospital of Women and Children, Qingdao, China
- Quan Sheng Xing, Qingdao University-Affiliated Hospital of Women and Children, tongfu road 6, shibei district, Qingdao 266000, China.
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Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther 2022; 7:3. [PMID: 34980884 PMCID: PMC8724284 DOI: 10.1038/s41392-021-00762-6] [Citation(s) in RCA: 1066] [Impact Index Per Article: 355.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/28/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis. The deregulation of Wnt/β-catenin signalling often leads to various serious diseases, including cancer and non-cancer diseases. Although many articles have reviewed Wnt/β-catenin from various aspects, a systematic review encompassing the origin, composition, function, and clinical trials of the Wnt/β-catenin signalling pathway in tumour and diseases is lacking. In this article, we comprehensively review the Wnt/β-catenin pathway from the above five aspects in combination with the latest research. Finally, we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment.
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Zahra MH, Nawara HM, Hassan G, Afify SM, Seno A, Seno M. Cancer Stem Cells Contribute to Drug Resistance in Multiple Different Ways. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1393:125-139. [PMID: 36587305 DOI: 10.1007/978-3-031-12974-2_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Many tumors are resistant to conventional cancer therapies because a tumor is composed of heterogeneous cell population. Especially, subpopulation of cancer stem cells, which have self-renewal and differentiation properties and responsible for the tumor initiation, is generally considered resistant to chemo-, radio-, and immune therapy. Understanding the mechanism of drug resistance in cancer stem cells should lead to establish more effective therapeutic strategies. Actually, different molecular mechanisms are conceivable for cancer stem cells acquiring drug resistance. These mechanisms include not only cytoplasmic signaling pathways but also the intercellular communications in the tumor microenvironment. Recently, a great deal of successful reports challenged to elucidate the mechanisms of drug resistance and to develop novel treatments targeting cancer stem cells.
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Affiliation(s)
- Maram H Zahra
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
| | - Hend M Nawara
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
| | - Ghmkin Hassan
- Department of Genomic Oncology and Oral Medicine, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Said M Afify
- Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin El Koum-Menoufia, Shebeen El-Kom, 32511, Egypt
| | - Akimasa Seno
- Laboratory of Natural Food & Medicine, Co., Ltd, Okayama University Incubator, Okayama, 700-8530, Japan
| | - Masaharu Seno
- Laboratory of Natural Food & Medicine, Co., Ltd, Okayama University Incubator, Okayama, 700-8530, Japan.
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Sohn SH, Sul HJ, Kim BJ, Kim HS, Zang DY. Entrectinib Induces Apoptosis and Inhibits the Epithelial-Mesenchymal Transition in Gastric Cancer with NTRK Overexpression. Int J Mol Sci 2021; 23:ijms23010395. [PMID: 35008821 PMCID: PMC8745632 DOI: 10.3390/ijms23010395] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/24/2021] [Accepted: 12/29/2021] [Indexed: 01/16/2023] Open
Abstract
Tropomyosin receptor kinase (TRK) and receptor tyrosine kinase (RTK class VII) expression are important in many human diseases, especially cancers, including colorectal, lung, and gastric cancer. Using RNA sequencing analysis, we evaluated the mRNA expression and mutation profiles of gastric cancer patients with neurotropic tropomyosin receptor kinase (NTRK) 1-3 overexpression (defined as a ≥2.0-fold change). Furthermore, we screened eight TRK inhibitors in NCI-N87, SNU16, MKN28, MKN7, and AGS cells. Among these inhibitors, entrectinib showed the highest inhibitory activity; therefore, this drug was selected for analysis of its therapeutic mechanisms in gastric cancer. Entrectinib treatment induced apoptosis in NTRK1-3-expressing and VEGFR2-expressing NCI-N87 and AGS cells, but it had no effect on NTRK1-3-, VEGFR2-, TGFBR1-, and CD274-expressing MKN7 cells. SNU16 and MKN28 cells with low NTRK1-3 expression were not affected by entrectinib. Therefore, a mechanistic study was conducted in NCI-N87 (high expression of NTRK1-3 but mutation of NTRK3), AGS (high expression of NTRK1-3) and MKN28 (low expression of NTRK1-3) gastric cancer cell lines. Entrectinib treatment significantly reduced expression levels of phosphorylated NFκB, AKT, ERK, and β-catenin in NCI-N87 and AGS cells, whereas it upregulated the expression levels of ECAD in NCI-N87 cells. Together, these results suggest that entrectinib has anti-cancer activity not only in GC cells overexpressing pan NTRK but also in VEGFR2 GC cells via the inhibition of the pan NTRK and VEGFR signaling pathways.
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Affiliation(s)
- Sung-Hwa Sohn
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.)
| | - Hee Jung Sul
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.)
| | - Bum Jun Kim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang 14068, Korea; (B.J.K.); (H.S.K.)
| | - Hyeong Su Kim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang 14068, Korea; (B.J.K.); (H.S.K.)
| | - Dae Young Zang
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.)
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang 14068, Korea; (B.J.K.); (H.S.K.)
- Correspondence: ; Tel.: +82-31-380-4167
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38
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Torres VI, Barrera DP, Varas-Godoy M, Arancibia D, Inestrosa NC. Selective Surface and Intraluminal Localization of Wnt Ligands on Small Extracellular Vesicles Released by HT-22 Hippocampal Neurons. Front Cell Dev Biol 2021; 9:735888. [PMID: 34722516 PMCID: PMC8548728 DOI: 10.3389/fcell.2021.735888] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022] Open
Abstract
The Wnt signaling pathway induces various responses underlying the development and maturation of the nervous system. Wnt ligands are highly hydrophobic proteins that limit their diffusion through an aqueous extracellular medium to a target cell. Nevertheless, their attachment to small extracellular vesicles-like exosomes is one of the described mechanisms that allow their transport under this condition. Some Wnt ligands in these vehicles are expected to be dependent on post-translational modifications such as acylation. The mechanisms determining Wnt loading in exosomes and delivery to the target cells are largely unknown. Here, we took advantage of a cell model that secret a highly enriched population of small extracellular vesicles (sEVs), hippocampal HT-22 neurons. First, to establish the cell model, we characterized the morphological and biochemical properties of an enriched fraction of sEVs obtained from hippocampal HT-22 neurons that express NCAM-L1, a specific exosomal neuronal marker. Transmission electron microscopy showed a highly enriched fraction of exosome-like vesicles. Next, the exosomal presence of Wnt3a, Wnt5a, and Wnt7a was confirmed by western blot analysis and electron microscopy combined with immunogold. Also, we studied whether palmitoylation is a necessary post-translational modification for the transport Wnt in these vesicles. We found that proteinase-K treatment of exosomes selectively decreased their Wnt5a and Wnt7a content, suggesting that their expression is delimited to the exterior membrane surface. In contrast, Wnt3a remained attached, suggesting that it is localized within the exosome lumen. On the other hand, Wnt-C59, a specific inhibitor of porcupine O-acyltransferase (PORCN), decreased the association of Wnt with exosomes, suggesting that Wnt ligand acylation is necessary for them to be secreted by exosomes. These findings may help to understand the action of the Wnt ligands in the target cell, which could be defined during the packaging of the ligands in the secretory cell sEVs.
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Affiliation(s)
- Viviana I Torres
- Departamento Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Daniela P Barrera
- Centro de Envejecimiento y Regeneración (CARE UC), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel Varas-Godoy
- Cancer Cell Biology Laboratory, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Duxan Arancibia
- Departamento Biomédico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile
| | - Nibaldo C Inestrosa
- Centro de Envejecimiento y Regeneración (CARE UC), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile
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Shi F, Mendrola JM, Sheetz JB, Wu N, Sommer A, Speer KF, Noordermeer JN, Kan ZY, Perry K, Englander SW, Stayrook SE, Fradkin LG, Lemmon MA. ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes. Cell Rep 2021; 37:109834. [PMID: 34686333 PMCID: PMC8650758 DOI: 10.1016/j.celrep.2021.109834] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/06/2021] [Accepted: 09/22/2021] [Indexed: 01/08/2023] Open
Abstract
WNTs play key roles in development and disease, signaling through Frizzled (FZD) seven-pass transmembrane receptors and numerous co-receptors including ROR and RYK family receptor tyrosine kinases (RTKs). We describe crystal structures and WNT-binding characteristics of extracellular regions from the Drosophila ROR and RYK orthologs Nrk (neurospecific receptor tyrosine kinase) and Derailed-2 (Drl-2), which bind WNTs though a FZD-related cysteine-rich domain (CRD) and WNT-inhibitory factor (WIF) domain respectively. Our crystal structures suggest that neither Nrk nor Drl-2 can accommodate the acyl chain typically attached to WNTs. The Nrk CRD contains a deeply buried bound fatty acid, unlikely to be exchangeable. The Drl-2 WIF domain lacks the lipid-binding site seen in WIF-1. We also find that recombinant DWnt-5 can bind Drosophila ROR and RYK orthologs despite lacking an acyl chain. Alongside analyses of WNT/receptor interaction sites, our structures provide further insight into how WNTs may recruit RTK co-receptors into signaling complexes.
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Affiliation(s)
- Fumin Shi
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jeannine M Mendrola
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Joshua B Sheetz
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
| | - Neo Wu
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Anselm Sommer
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
| | - Kelsey F Speer
- Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Medicine (Hematology-Oncology), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jasprina N Noordermeer
- Molecular Cell Biology, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands
| | - Zhong-Yuan Kan
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Kay Perry
- NE-CAT, Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, IL 60439, USA
| | - S Walter Englander
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Steven E Stayrook
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
| | - Lee G Fradkin
- Molecular Cell Biology, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands; Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Mark A Lemmon
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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40
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Perkins RS, Suthon S, Miranda-Carboni GA, Krum SA. WNT5B in cellular signaling pathways. Semin Cell Dev Biol 2021; 125:11-16. [PMID: 34635443 DOI: 10.1016/j.semcdb.2021.09.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 12/31/2022]
Abstract
The Wnt signaling ligand WNT5B is implicated in various developmental pathways, both in normal and pathological physiology. Most of the research on WNT5B has been associated with expression analysis and disease states, leaving the signaling pathways underexplored. Here, we review the current understandings of WNT5B's regulation of signal transduction, from receptors to downstream mediators and transcription factors. We also describe its roles in β-catenin-dependent and β-catenin-independent (Planar Cell Polarity and Wnt/Ca2+) Wnt signaling.
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Affiliation(s)
- Rachel S Perkins
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Sarocha Suthon
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Gustavo A Miranda-Carboni
- Department of Medicine, Division of Hematology and Oncology, University of Tennessee Health Science Center, Memphis, TN, USA; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Susan A Krum
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
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41
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Vaivads M, Akota I, Pilmane M. PAX7, PAX9 and RYK Expression in Cleft Affected Tissue. MEDICINA-LITHUANIA 2021; 57:medicina57101075. [PMID: 34684112 PMCID: PMC8540985 DOI: 10.3390/medicina57101075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/29/2021] [Accepted: 10/06/2021] [Indexed: 11/25/2022]
Abstract
Background and Objectives: Cleft lip with or without cleft palate is one of the most common types of congenital malformations. Transcription factors paired box 7 and 9 (PAX7, PAX9) and receptor-like tyrosine kinase (RYK) have been previously associated with the formation of orofacial clefts but their exact possible involvement and interactions in the tissue of specific cleft types remains uncertain. There is a limited number of morphological studies analyzing these specific factors in cleft affected tissue due to ethical aspects and the limited amount of available tissue material. This study analyses the presence of PAX7, PAX9, and RYK immunopositive structures within different cleft affected tissue to assess their possible involvement in cleft morphopathogenesis. Materials and Methods: Cleft affected tissue was collected from non-syndromic orofacial cleft patients during cleft correcting surgery (36 patients with unilateral cleft lip, 13 patients with bilateral cleft lip, 26 patients with isolated cleft palate). Control group oral cavity tissue was obtained from 7 patients without cleft lip and palate. To evaluate the number of immunopositive structures in the cleft affected tissue and the control group, a semiquantitative counting method was used. Non-parametric statistical methods (Kruskal–Wallis H test, Mann–Whitney U test, and Spearman’s rank correlation) were used. Results: Statistically significant differences for the number of PAX7, PAX9, and RYK-positive cells were notified between the controls and the patient groups. Multiple statistically significant correlations between the factors were found in each cleft affected tissue group. Conclusions: PAX7, PAX9, and RYK have a variable involvement and interaction in postnatal morphopathogenesis of orofacial clefts. PAX7 is more associated with the formation of unilateral cleft lip, while PAX9 relates more towards the isolated cleft palate. The stable presence of RYK in all cleft types indicates its possible participation in different facial cleft formations.
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Affiliation(s)
- Mārtiņš Vaivads
- Department of Morphology, Institute of Anatomy and Anthropology, Riga Stradins University, Kronvalda Boulevard 9, LV-1010 Riga, Latvia;
- Correspondence:
| | - Ilze Akota
- Department of Oral and Maxillofacial Surgery, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia;
- Cleft Lip and Palate Centre, Institute of Stomatology, Riga Stradins University, 20 Dzirciema Street, LV-1007 Riga, Latvia
| | - Māra Pilmane
- Department of Morphology, Institute of Anatomy and Anthropology, Riga Stradins University, Kronvalda Boulevard 9, LV-1010 Riga, Latvia;
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Ka C, Gautam S, Marshall SR, Tice LP, Martinez-Bartolome M, Fenner JL, Range RC. Receptor Tyrosine Kinases ror1/2 and ryk Are Co-expressed with Multiple Wnt Signaling Components During Early Development of Sea Urchin Embryos. THE BIOLOGICAL BULLETIN 2021; 241:140-157. [PMID: 34706206 PMCID: PMC11257382 DOI: 10.1086/715237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
AbstractA combination of receptors, co-receptors, and secreted Wnt modulators form protein complexes at the cell surface that activate one or more of the three different Wnt signaling pathways (Wnt/β-catenin, Wnt/JNK, and Wnt/Ca2+). Two or more of these pathways are often active in the same cellular territories, forming Wnt signaling networks; however, the molecular mechanisms necessary to integrate information from these pathways in these situations are unclear in any in vivo model system. Recent studies have implicated two Wnt binding receptor tyrosine kinases, receptor tyrosine kinase-like orphan receptor (Ror) and related-to-receptor tyrosine kinase (Ryk), in the regulation of canonical and non-canonical Wnt signaling pathways, depending on the context; however, the spatiotemporal expression of these genes in relation to Wnt signaling components has not been well characterized in most deuterostome model systems. Here we use a combination of phylogenetic and spatiotemporal gene expression analyses to characterize Ror and Ryk orthologs in sea urchin embryos. Our phylogenetic analysis indicates that both ror1/2 and ryk originated as single genes from the metazoan ancestor. Expression analyses indicate that ror1/2 and ryk are expressed in the same domains of many Wnt ligands and Frizzled receptors essential for the specification and patterning of germ layers along the early anterior-posterior axis. In addition, both genes are co-expressed with Wnt signaling components in the gut, ventral ectoderm, and anterior neuroectoderm territories later in development. Together, our results indicate that Ror and Ryk have a complex evolutionary history and that their spatiotemporal expression suggests that they could contribute to the complexity of Wnt signaling in early sea urchin embryogenesis.
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Affiliation(s)
- C Ka
- Department of Biological Sciences, Auburn University, Auburn, Alabama 36849
| | - S Gautam
- Department of Biological Sciences, Auburn University, Auburn, Alabama 36849
| | - SR Marshall
- Department of Biological Sciences, Mississippi State University, Mississippi State, MS 39762
| | - LP Tice
- Department of Biological Sciences, Mississippi State University, Mississippi State, MS 39762
| | | | - JL Fenner
- Department of Biological Sciences, Auburn University, Auburn, Alabama 36849
| | - RC Range
- Department of Biological Sciences, Auburn University, Auburn, Alabama 36849
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On the Common Journey of Neural Cells through Ischemic Brain Injury and Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22189689. [PMID: 34575845 PMCID: PMC8472292 DOI: 10.3390/ijms22189689] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/19/2021] [Accepted: 09/03/2021] [Indexed: 01/09/2023] Open
Abstract
Ischemic brain injury and Alzheimer's disease (AD) both lead to cell death in the central nervous system (CNS) and thus negatively affect particularly the elderly population. Due to the lack of a definitive cure for brain ischemia and AD, it is advisable to carefully study, compare, and contrast the mechanisms that trigger, and are involved in, both neuropathologies. A deeper understanding of these mechanisms may help ameliorate, or even prevent, the destructive effects of neurodegenerative disorders. In this review, we deal with ischemic damage and AD, with the main emphasis on the common properties of these CNS disorders. Importantly, we discuss the Wnt signaling pathway as a significant factor in the cell fate determination and cell survival in the diseased adult CNS. Finally, we summarize the interesting findings that may improve or complement the current sparse and insufficient treatments for brain ischemia and AD, and we delineate prospective directions in regenerative medicine.
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44
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Mehta S, Hingole S, Chaudhary V. The Emerging Mechanisms of Wnt Secretion and Signaling in Development. Front Cell Dev Biol 2021; 9:714746. [PMID: 34485301 PMCID: PMC8415634 DOI: 10.3389/fcell.2021.714746] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/20/2021] [Indexed: 12/22/2022] Open
Abstract
Wnts are highly-conserved lipid-modified secreted proteins that activate multiple signaling pathways. These pathways regulate crucial processes during various stages of development and maintain tissue homeostasis in adults. One of the most fascinating aspects of Wnt protein is that despite being hydrophobic, they are known to travel several cell distances in the extracellular space. Research on Wnts in the past four decades has identified several factors and uncovered mechanisms regulating their expression, secretion, and mode of extracellular travel. More recently, analyses on the importance of Wnt protein gradients in the growth and patterning of developing tissues have recognized the complex interplay of signaling mechanisms that help in maintaining tissue homeostasis. This review aims to present an overview of the evidence for the various modes of Wnt protein secretion and signaling and discuss mechanisms providing precision and robustness to the developing tissues.
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Affiliation(s)
| | | | - Varun Chaudhary
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, India
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45
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Teo S, Salinas PC. Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation. Front Mol Neurosci 2021; 14:683035. [PMID: 34194299 PMCID: PMC8236581 DOI: 10.3389/fnmol.2021.683035] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/17/2021] [Indexed: 11/26/2022] Open
Abstract
The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation.
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Affiliation(s)
| | - Patricia C. Salinas
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
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WNT5A inhibition alters the malignant peripheral nerve sheath tumor microenvironment and enhances tumor growth. Oncogene 2021; 40:4229-4241. [PMID: 34079083 PMCID: PMC8217297 DOI: 10.1038/s41388-021-01773-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 12/21/2020] [Accepted: 03/29/2021] [Indexed: 02/05/2023]
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas that cause significant mortality in adults with neurofibromatosis type 1. We compared gene expression of growth factors in normal human nerves to MPNST and normal human Schwann cells to MPNST cell lines. We identified WNT5A as the most significantly upregulated ligand-coding gene and verified its protein expression in MPNST cell lines and tumors. In many contexts WNT5A acts as an oncogene. However, inhibiting WNT5A expression using shRNA did not alter MPNST cell proliferation, invasion, migration, or survival in vitro. Rather, shWNT5A-treated MPNST cells upregulated mRNAs associated with the remodeling of extracellular matrix and with immune cell communication. In addition, these cells secreted increased amounts of the proinflammatory cytokines CXCL1, CCL2, IL6, CXCL8, and ICAM1. Versus controls, shWNT5A-expressing MPNST cells formed larger tumors in vivo. Grafted tumors contained elevated macrophage/stromal cells, larger and more numerous blood vessels, and increased levels of Mmp9, Cxcl13, Lipocalin-1, and Ccl12. In some MPNST settings, these effects were mimicked by targeting the WNT5A receptor ROR2. These data suggest that the non-canonical Wnt ligand WNT5A inhibits MPNST tumor formation by modulating the MPNST microenvironment, so that blocking WNT5A accelerates tumor growth in vivo.
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El Sabeh M, Saha SK, Afrin S, Islam MS, Borahay MA. Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities. Mol Cell Biochem 2021; 476:3513-3536. [PMID: 33999334 DOI: 10.1007/s11010-021-04174-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Uterine leiomyoma is the most common tumor of the female reproductive system and originates from a single transformed myometrial smooth muscle cell. Despite the immense medical, psychosocial, and financial impact, the exact underlying mechanisms of leiomyoma pathobiology are poorly understood. Alterations of signaling pathways are thought to be instrumental in leiomyoma biology. Wnt/β-catenin pathway appears to be involved in several aspects of the genesis of leiomyomas. For example, Wnt5b is overexpressed in leiomyoma, and the Wnt/β-catenin pathway appears to mediate the role of MED12 mutations, the most common mutations in leiomyoma, in tumorigenesis. Moreover, Wnt/β-catenin pathway plays a paracrine role where estrogen/progesterone treatment of mature myometrial or leiomyoma cells leads to increased expression of Wnt11 and Wnt16, which induces proliferation of leiomyoma stem cells and tumor growth. Constitutive activation of β-catenin leads to myometrial hyperplasia and leiomyoma-like lesions in animal models. Wnt/β-catenin signaling is also closely involved in mechanotransduction and extracellular matrix regulation and relevant alterations in leiomyoma, and crosstalk is noted between Wnt/β-catenin signaling and other pathways known to regulate leiomyoma development and growth such as estrogen, progesterone, TGFβ, PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, IGF, Hippo, and Notch signaling. Finally, evidence suggests that inhibition of the canonical Wnt pathway using β-catenin inhibitors inhibits leiomyoma cell proliferation. Understanding the molecular mechanisms of leiomyoma development is essential for effective treatment. The specific Wnt/β-catenin pathway molecules discussed in this review constitute compelling candidates for therapeutic targeting.
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Affiliation(s)
- Malak El Sabeh
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
| | - Subbroto Kumar Saha
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
| | - Sadia Afrin
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
| | - Md Soriful Islam
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
| | - Mostafa A Borahay
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
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Bayle E, Svensson F, Atkinson BN, Steadman D, Willis NJ, Woodward HL, Whiting P, Vincent JP, Fish PV. Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling. J Med Chem 2021; 64:4289-4311. [PMID: 33783220 PMCID: PMC8172013 DOI: 10.1021/acs.jmedchem.0c01974] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Indexed: 12/12/2022]
Abstract
Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.
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Affiliation(s)
- Elliott
D. Bayle
- Alzheimer’s
Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
- The
Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
| | - Fredrik Svensson
- Alzheimer’s
Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
- The
Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
| | - Benjamin N. Atkinson
- Alzheimer’s
Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
| | - David Steadman
- Alzheimer’s
Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
| | - Nicky J. Willis
- Alzheimer’s
Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
| | - Hannah L. Woodward
- Alzheimer’s
Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
| | - Paul Whiting
- Alzheimer’s
Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
| | - Jean-Paul Vincent
- The
Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
| | - Paul V. Fish
- Alzheimer’s
Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
- The
Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
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Colozza G, Koo BK. Wnt/β-catenin signaling: Structure, assembly and endocytosis of the signalosome. Dev Growth Differ 2021; 63:199-218. [PMID: 33619734 PMCID: PMC8251975 DOI: 10.1111/dgd.12718] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/01/2021] [Accepted: 02/17/2021] [Indexed: 12/12/2022]
Abstract
Wnt/β‐catenin signaling is an ancient pathway that regulates key aspects of embryonic development, cell differentiation, proliferation, and adult stem cell homeostasis. Work from different laboratories has shed light on the molecular mechanisms underlying the Wnt pathway, including structural details of ligand–receptor interactions. One key aspect that has emerged from multiple studies is that endocytosis of the receptor complex plays a crucial role in fine‐tuning Wnt/β‐catenin signaling. Endocytosis is a key process involved in both activation as well as attenuation of Wnt signaling, but how this is regulated is still poorly understood. Importantly, recent findings show that Wnt also regulates central metabolic pathways such as the acquisition of nutrients through actin‐driven endocytic mechanisms. In this review, we propose that the Wnt pathway displays diverse characteristics that go beyond the regulation of gene expression, through a connection with the endocytic machinery.
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Affiliation(s)
- Gabriele Colozza
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria
| | - Bon-Kyoung Koo
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria
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Dolmatov IY. Molecular Aspects of Regeneration Mechanisms in Holothurians. Genes (Basel) 2021; 12:250. [PMID: 33578707 PMCID: PMC7916379 DOI: 10.3390/genes12020250] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/05/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
Holothurians, or sea cucumbers, belong to the phylum Echinodermata. They show good regenerative abilities. The present review provides an analysis of available data on the molecular aspects of regeneration mechanisms in holothurians. The genes and signaling pathways activated during the asexual reproduction and the formation of the anterior and posterior parts of the body, as well as the molecular mechanisms that provide regeneration of the nervous and digestive systems, are considered here. Damage causes a strong stress response, the signs of which are recorded even at late regeneration stages. In holothurian tissues, the concentrations of reactive oxygen species and antioxidant enzymes increase. Furthermore, the cellular and humoral components of the immune system are activated. Extracellular matrix remodeling and Wnt signaling play a major role in the regeneration in holothurians. All available morphological and molecular data show that the dedifferentiation of specialized cells in the remnant of the organ and the epithelial morphogenesis constitute the basis of regeneration in holothurians. However, depending on the type of damage, the mechanisms of regeneration may differ significantly in the spatial organization of regeneration process, the involvement of different cell types, and the depth of reprogramming of their genome (dedifferentiation or transdifferentiation).
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Affiliation(s)
- Igor Yu Dolmatov
- A.V. Zhirmunsky National Scientifc Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevsky 17, 690041 Vladivostok, Russia
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