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1
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Aksan B, Mauceri D. Beyond vessels: unraveling the impact of VEGFs on neuronal functions and structure. J Biomed Sci 2025; 32:33. [PMID: 40050849 PMCID: PMC11884128 DOI: 10.1186/s12929-025-01128-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/21/2025] [Indexed: 03/10/2025] Open
Abstract
Neurons rely on the bloodstream for essential nutrients and oxygen, which is facilitated by an intricate coupling of the neuronal and vascular systems. Central to this neurovascular interaction is the vascular endothelial growth factor (VEGF) family, a group of secreted growth factors traditionally known for their roles in promoting endothelial cell proliferation, migration, and survival in the cardiovascular and lymphatic systems. However, emerging evidence shows that VEGFs also play indispensable roles in the nervous system, extending beyond their canonical angiogenic and lymphangiogenic functions. Over the past two decades, VEGFs have been found to exert direct effects on neurons, influencing key aspects of neuronal function independently of their actions on vascular cells. In particular, it has become increasingly evident that VEGFs also play crucial functions in the development, regulation, and maintenance of neuronal morphology. Understanding the roles of VEGFs in neuronal development is of high scientific and clinical interest because of the significance of precise neuronal morphology for neural connectivity and network function, as well as the association of morphological abnormalities with neurological and neurodegenerative disorders. This review begins with an overview of the VEGF family members, their structural characteristics, receptors, and established roles in vasculature. However, it then highlights and focuses on the exciting variety of neuronal functions of VEGFs, especially their crucial role in the development, regulation, and maintenance of neuronal morphology.
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Affiliation(s)
- Bahar Aksan
- Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, INF 366, 69120, Heidelberg, Germany
| | - Daniela Mauceri
- Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, INF 366, 69120, Heidelberg, Germany.
- Institute of Anatomy and Cell Biology, Dept. Molecular and Cellular Neuroscience, University of Marburg, Robert-Koch-Str. 8, 35032, Marburg, Germany.
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2
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Hendrickson WA, Gong Z. Structural and evolutionary insights into the functioning of glycoprotein hormones and their receptors. Andrology 2025. [PMID: 39871527 DOI: 10.1111/andr.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 01/02/2025] [Accepted: 01/16/2025] [Indexed: 01/29/2025]
Abstract
The neuroendocrine system that comprises the glycoprotein hormones (GpHs) and their receptors is essential for reproduction and metabolism. Each GpH hormone is an αβ heterodimer of cystine-knot proteins and its cognate receptor is a G-protein coupled receptor (GPCR) distinguished by a large leucine-rich-repeat (LRR) extracellular domain that binds the hormone and a class A GPCR transmembrane domain that signals through an associating heterotrimeric G protein. Hence, the receptors are called LRR-containing GPCRs-LGRs. The vertebrate GpHs and LGRs have co-evolved from homologs in the earliest metazoan animals, including sponges and comb jellies, but these are absent from unicellular organisms and plants. The two GpH subunits and accompanying LGR receptor of the nematode Caenorhabditis elegans are representative of the invertebrate evolutionary predecessors of human GpH proteins and their receptors, for example follicle-stimulating hormone (FSH) and the FSH receptor (FSHR). Atomic structures of the human GpHs and their receptors, which have been determined by X-ray crystallography and cryogenic electron microscopy (cryo-EM), inform the evolutionary process and provide a mechanistic understanding of the transmission of biochemical signals of hormone binding at the cell surface to the elicitation of second messengers such as cyclic AMP in the cytoplasm. There is compelling biochemical and cellular evidence for the importance of receptor dimers in GpH signaling in cells; yet, all of the human receptors are monomeric as defined beautifully by cryo-EM. Fortunately, the LGR of C. elegans is a stable dimer and its structure, when analyzed in the context of structural information from the human counterparts, predicts a hypothetical model for functionally relevant dimeric associations of the human GpH receptors.
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Affiliation(s)
- Wayne A Hendrickson
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA
- Department of Physiology and Cellular Biophysics, Columbia University, New York, New York, USA
| | - Zhen Gong
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA
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3
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Saran A, Nishizaki D, Lippman SM, Kato S, Kurzrock R. Interleukin-17: A pleiotropic cytokine implicated in inflammatory, infectious, and malignant disorders. Cytokine Growth Factor Rev 2025:S1359-6101(25)00002-4. [PMID: 39875232 DOI: 10.1016/j.cytogfr.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025]
Abstract
IL-17A, referred to as IL-17, is the founding member of a family of pro-inflammatory cytokines, including IL-17B, IL-17C, IL-17D, IL-17E (or IL-25), and IL-17F, which act via receptors IL-17RA to IL-17RE, and elicit potent cellular responses that impact diverse diseases. IL-17's interactions with various cytokines include forming a heterodimer with IL-17F and being stimulated by IL-23's activation of Th17 cells, which can lead to inflammation and autoimmunity. IL-17 is implicated in infectious diseases and inflammatory disorders such as rheumatoid arthritis and psoriasis, promoting neutrophil recruitment and anti-bacterial immunity, but potentially exacerbating fungal and viral infections, revealing its dual role as protective and pathologic. IL-17 is also involved in various cancers, including breast, colon, cervical, prostate, and skin cancer, contributing to proliferation, immune invasion, and metastases, but also playing a protective role in certain instances. Four FDA-approved drugs-secukinumab (for ankylosing spondylitis, enthesitis-related arthritis, hidradenitis suppurativa, non-radiographic axial spondyloarthritis, plaque psoriasis, and psoriatic arthritis), ixekizumab (for ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis, and psoriatic arthritis), brodalumab (for plaque psoriasis), and bimekizumab (for plaque psoriasis)-suppress the IL-17 pathway, with more in development, including netakimab, sonelokimab, izokibep, and CJM112. These agents and others are being studied across a spectrum of disorders. Understanding the complicated interplay between IL-17 and other immune mediators may yield new treatments for inflammatory/autoimmune conditions and malignancies.
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Affiliation(s)
| | - Daisuke Nishizaki
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, CA, USA; Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Scott M Lippman
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, CA, USA; Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Shumei Kato
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, CA, USA; Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
| | - Razelle Kurzrock
- MCW Cancer Center and Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA; WIN Consortium, Paris, France; University of Nebraska, Lincoln, NE, USA.
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Petrella C, Ferraguti G, Tarani L, Tarani F, Messina MP, Fiore M. Nerve Growth Factor and Brain-Derived Neurotrophic Factor in COVID-19. BIOLOGY 2024; 13:907. [PMID: 39596862 PMCID: PMC11591877 DOI: 10.3390/biology13110907] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/29/2024] [Accepted: 11/02/2024] [Indexed: 11/29/2024]
Abstract
Neurotrophins (NTs) constitute a family of small protein messengers that play a fundamental role in both the central and peripheral nervous systems. In particular, the nerve growth factor (NGF) and the brain-derived neurotrophic factor (BDNF) play a subtle role in the survival, differentiation, and functioning of neuronal populations, as well as in the fine regulation of immune functions. The SARS-CoV-2 infection was characterized by a sequela of symptoms (serious respiratory pathology, inflammatory storm, neurological discomfort, up to the less serious flu-like symptoms), which caused, at the end of 2023, more than 7 million deaths worldwide. Despite the official end of the pandemic, the physical and psychological consequences are currently the object of scientific research, both acute and chronic/long-lasting (Long-COVID-19). Given the multifactorial nature of the outcomes of SARS-CoV-2 infection in adults and children, several studies have investigated the potential involvement of the NGF and BDNF systems in the pathology. This narrative review aims to summarize the most recent evidence on this crucial topic.
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Affiliation(s)
- Carla Petrella
- Institute of Biochemistry and Cell Biology (IBBC-CNR), Via E. Ramarini, 32, Monterotondo Scalo, 00015 Rome, Italy
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Luigi Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (L.T.); (F.T.); (M.P.M.)
| | - Francesca Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (L.T.); (F.T.); (M.P.M.)
| | - Marisa Patrizia Messina
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (L.T.); (F.T.); (M.P.M.)
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology (IBBC-CNR), Via E. Ramarini, 32, Monterotondo Scalo, 00015 Rome, Italy
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5
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Chen S, Fan H, Ran C, Hong Y, Feng H, Yue Z, Zhang H, Pontarotti P, Xu A, Huang S. The IL-17 pathway intertwines with neurotrophin and TLR/IL-1R pathways since its domain shuffling origin. Proc Natl Acad Sci U S A 2024; 121:e2400903121. [PMID: 38683992 PMCID: PMC11087794 DOI: 10.1073/pnas.2400903121] [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: 02/02/2024] [Accepted: 03/11/2024] [Indexed: 05/02/2024] Open
Abstract
The IL-17 pathway displays remarkably diverse functional modes between different subphyla, classes, and even orders, yet its driving factors remains elusive. Here, we demonstrate that the IL-17 pathway originated through domain shuffling between a Toll-like receptor (TLR)/IL-1R pathway and a neurotrophin-RTK (receptor-tyrosine-kinase) pathway (a Trunk-Torso pathway). Unlike other new pathways that evolve independently, the IL-17 pathway remains intertwined with its donor pathways throughout later evolution. This intertwining not only influenced the gains and losses of domains and components in the pathway but also drove the diversification of the pathway's functional modes among animal lineages. For instance, we reveal that the crustacean female sex hormone, a neurotrophin inducing sex differentiation, could interact with IL-17Rs and thus be classified as true IL-17s. Additionally, the insect prothoracicotropic hormone, a neurotrophin initiating ecdysis in Drosophila by binding to Torso, could bind to IL-17Rs in other insects. Furthermore, IL-17R and TLR/IL-1R pathways maintain crosstalk in amphioxus and zebrafish. Moreover, the loss of the Death domain in the pathway adaptor connection to IκB kinase and stress-activated protein kinase (CIKSs) dramatically reduced their abilities to activate nuclear factor-kappaB (NF-κB) and activator protein 1 (AP-1) in amphioxus and zebrafish. Reinstating this Death domain not only enhanced NF-κB/AP-1 activation but also strengthened anti-bacterial immunity in zebrafish larvae. This could explain why the mammalian IL-17 pathway, whose CIKS also lacks Death, is considered a weak signaling activator, relying on synergies with other pathways. Our findings provide insights into the functional diversity of the IL-17 pathway and unveil evolutionary principles that could govern the pathway and be used to redesign and manipulate it.
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Affiliation(s)
- Shenghui Chen
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao266237, China
| | - Huiping Fan
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
| | - Chenrui Ran
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
| | - Yun Hong
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
| | - Huixiong Feng
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
| | - Zirui Yue
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
| | - Hao Zhang
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
| | - Pierre Pontarotti
- MEPHI (Microbes, Evolution, Phylogénie et Infection), Aix Marseille Université, Marseille, France
| | - Anlong Xu
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing100029, China
| | - Shengfeng Huang
- State Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou510275, China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao266237, China
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Tian S, de Veer SJ, Durek T, Wang CK, Craik DJ. Nucleation of a key beta-turn promotes cyclotide oxidative folding. J Biol Chem 2024; 300:107125. [PMID: 38432638 PMCID: PMC10999817 DOI: 10.1016/j.jbc.2024.107125] [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: 11/07/2023] [Revised: 02/05/2024] [Accepted: 02/19/2024] [Indexed: 03/05/2024] Open
Abstract
Cyclotides are plant-derived peptides characterized by a head-to-tail cyclic backbone and a cystine knot motif comprised of three disulfide bonds. Formation of this motif via in vitro oxidative folding can be challenging and can result in misfolded isomers with nonnative disulfide connectivities. Here, we investigated the effect of β-turn nucleation on cyclotide oxidative folding. Two types of β-turn mimics were grafted into kalata B1, individually replacing each of the four β-turns in the folded cyclotide. Insertion of d-Pro-Gly into loop 5 was beneficial to the folding of both cyclic kB1 and a linear form of the peptide. The linear grafted analog folded four-times faster in aqueous conditions than cyclic kB1 in optimized conditions. Additionally, the cyclic analogue folded without the need for redox agents by transitioning through a native-like intermediate that was on-pathway to product formation. Kalata B1 is from the Möbius subfamily of cyclotides. Grafting d-Pro-Gly into loop 5 of cyclotides from two other subfamilies also had a beneficial effect on folding. Our findings demonstrate the importance of a β-turn nucleation site for cyclotide oxidative folding, which could be adopted as a chemical strategy to improve the in vitro folding of diverse cystine-rich peptides.
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Affiliation(s)
- Sixin Tian
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia
| | - Simon J de Veer
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia
| | - Thomas Durek
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia
| | - Conan K Wang
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia
| | - David J Craik
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia.
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7
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Fox SC, Waskiewicz AJ. Transforming growth factor beta signaling and craniofacial development: modeling human diseases in zebrafish. Front Cell Dev Biol 2024; 12:1338070. [PMID: 38385025 PMCID: PMC10879340 DOI: 10.3389/fcell.2024.1338070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/18/2024] [Indexed: 02/23/2024] Open
Abstract
Humans and other jawed vertebrates rely heavily on their craniofacial skeleton for eating, breathing, and communicating. As such, it is vital that the elements of the craniofacial skeleton develop properly during embryogenesis to ensure a high quality of life and evolutionary fitness. Indeed, craniofacial abnormalities, including cleft palate and craniosynostosis, represent some of the most common congenital abnormalities in newborns. Like many other organ systems, the development of the craniofacial skeleton is complex, relying on specification and migration of the neural crest, patterning of the pharyngeal arches, and morphogenesis of each skeletal element into its final form. These processes must be carefully coordinated and integrated. One way this is achieved is through the spatial and temporal deployment of cell signaling pathways. Recent studies conducted using the zebrafish model underscore the importance of the Transforming Growth Factor Beta (TGF-β) and Bone Morphogenetic Protein (BMP) pathways in craniofacial development. Although both pathways contain similar components, each pathway results in unique outcomes on a cellular level. In this review, we will cover studies conducted using zebrafish that show the necessity of these pathways in each stage of craniofacial development, starting with the induction of the neural crest, and ending with the morphogenesis of craniofacial elements. We will also cover human skeletal and craniofacial diseases and malformations caused by mutations in the components of these pathways (e.g., cleft palate, craniosynostosis, etc.) and the potential utility of zebrafish in studying the etiology of these diseases. We will also briefly cover the utility of the zebrafish model in joint development and biology and discuss the role of TGF-β/BMP signaling in these processes and the diseases that result from aberrancies in these pathways, including osteoarthritis and multiple synostoses syndrome. Overall, this review will demonstrate the critical roles of TGF-β/BMP signaling in craniofacial development and show the utility of the zebrafish model in development and disease.
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Saadalla A, Seheult J, Pruthi RK, Chen D. Von Willebrand Factor Multimer Analysis and Classification: A Comprehensive Review and Updates. Semin Thromb Hemost 2023; 49:580-591. [PMID: 36174612 DOI: 10.1055/s-0042-1757183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Von Willebrand factor (VWF) is a multimeric glycoprotein with essential roles in primary hemostasis. Patients with von Willebrand disease (VWD), due to quantitative and/or qualitative defects of VWF usually experience mucocutaneous bleeding. Based on the laboratory results of VWF antigen, various VWF activities, factor VIII activity, and VWF multimer patterns, VWD can be categorized as type 1, 2, and 3 VWD. VWF multimer analysis by either manual or semi-automated electrophoresis and immunoblotting is a critical part of the laboratory testing to differentiate type 1, type 2 VWD, and subtypes of type 1 or 2 VWD. The multimer distribution patterns can also help to understand the underlying molecular mechanism of VWF synthesis, multimerization, and clearance defects in VWD. This review will cover VWF synthesis, multimerization, secretion, VWF multimer analysis, and VWF multimer interpretation of various types and subtypes of VWD.
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Affiliation(s)
- Abdulrahman Saadalla
- Department of Pathology, University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, Utah
| | - Jansen Seheult
- Division of Hematopathology, Special Coagulation Laboratory, Mayo Clinic, Rochester, Minnesota
| | - Rajiv K Pruthi
- Division of Hematopathology, Special Coagulation Laboratory, Mayo Clinic, Rochester, Minnesota
| | - Dong Chen
- Division of Hematopathology, Special Coagulation Laboratory, Mayo Clinic, Rochester, Minnesota
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Monsen VT, Attramadal H. Structural insights into regulation of CCN protein activities and functions. J Cell Commun Signal 2023:10.1007/s12079-023-00768-5. [PMID: 37245184 DOI: 10.1007/s12079-023-00768-5] [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: 02/15/2023] [Accepted: 05/07/2023] [Indexed: 05/29/2023] Open
Abstract
CCN proteins play important functions during development, in repair mechanisms following tissue injury, as well as in pathophysiologic mechanisms of metastasis of cancer. CCNs are secreted proteins that have a multimodular structure and are categorized as matricellular proteins. Although the prevailing view is that CCN proteins regulate biologic processes by interacting with a wide array of other proteins in the microenvironment of the extracellular matrix, the molecular mechanisms of action of CCN proteins are still poorly understood. Not dissuading the current view, however, the recent appreciation that these proteins are signaling proteins in their own right and may even be considered preproproteins controlled by endopeptidases to release a C-terminal bioactive peptide has opened new avenues of research. Also, the recent resolution of the crystal structure of two of the domains of CCN3 have provided new knowledge with implications for the entire CCN family. These resolved structures in combination with structural predictions based upon the AlphaFold artificial intelligence tool provide means to shed new light on CCN functions in context of the notable literature in the field. CCN proteins have emerged as important therapeutic targets in several disease conditions, and clinical trials are currently ongoing. Thus, a review that critically discusses structure - function relationship of CCN proteins, in particular as it relates to interactions with other proteins in the extracellular milieu and on the cell surface, as well as to cell signaling activities of these proteins, is very timely. Suggested mechanism for activation and inhibition of signaling by the CCN protein family (graphics generated with BioRender.com ).
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Affiliation(s)
- Vivi Talstad Monsen
- Institute for Surgical Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Håvard Attramadal
- Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
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Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther 2023; 8:198. [PMID: 37169756 PMCID: PMC10175505 DOI: 10.1038/s41392-023-01460-1] [Citation(s) in RCA: 408] [Impact Index Per Article: 204.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/20/2023] [Accepted: 04/20/2023] [Indexed: 05/13/2023] Open
Abstract
Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology, various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.
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Affiliation(s)
- Zhen-Ling Liu
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Huan-Huan Chen
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Li Zheng
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Ping Sun
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
| | - Lei Shi
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
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11
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Vafopoulou X, Donaldson LW, Steel CGH. The prothoracicotropic hormone (PTTH) of Rhodnius prolixus (Hemiptera) is noggin-like: Molecular characterisation, functional analysis and evolutionary implications. Gen Comp Endocrinol 2023; 332:114184. [PMID: 36455643 DOI: 10.1016/j.ygcen.2022.114184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/10/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022]
Abstract
Prothoracicotropic hormone (PTTH) is a central regulator of insect development that regulates the production of the steroid moulting hormones (ecdysteroids) from the prothoracic glands (PGs). Rhodnius PTTH was the first brain neurohormone discovered in any animal almost 100 years ago but has eluded identification and no homologue of Bombyx mori PTTH occurs in its genome. Here, we report Rhodnius PTTH is the first noggin-like PTTH found. It differs in important respects from known PTTHs and is the first PTTH from the Hemimetabola (Exopterygota) to be fully analysed. Recorded PTTHs are widespread in Holometabola but close to absent in hemimetabolous orders. We concluded Rhodnius PTTH likely differed substantially from the known ones. We identified one Rhodnius gene that coded a noggin-like protein (as defined by Molina et al., 2009) that had extensive similarities with known PTTHs but also had two additional cysteines. Sequence and structural analysis showed known PTTHs are closely related to noggin-like proteins, as both possess a growth factor cystine knot preceded by a potential cleavage site. The gene is significantly expressed only in the brain, in a few cells of the dorsal protocerebrum. We vector-expressed the sequence from the potential cleavage site to the C-terminus. This protein was strongly steroidogenic on PGs in vitro. An antiserum to the protein removed the steroidogenic protein released by the brain. RNAi performed on brains in vitro showed profound suppression of transcription of the gene and of production and release of PTTH and thus of ecdysteroid production by PGs. In vivo, the gene is expressed throughout development, in close synchrony with PTTH release, ecdysteroid production by PGs and the ecdysteroid titre. The Rhodnius PTTH monomer is 17kDa and immunoreactive to anti-PTTH of Bombyx mori (a holometabolan). Bombyx PTTH also mildly stimulated Rhodnius PGs. The two additional cysteines form a disulfide at the tip of finger 2, causing a loop of residues to protrude from the finger. A PTTH variant without this loop failed to stimulate PGs, showing the loop is essential for PTTH activity. It is considered that PTTHs of Holometabola evolved from a noggin-like protein in the ancestor of Holometabola and Hemiptera, c.400ma, explaining the absence of holometabolous-type PTTHs from hemimetabolous orders and the differences of Rhodnius PTTH from them. Noggin-like proteins studied from Hemiptera to Arachnida were homologous with Rhodnius PTTH and may be common as PTTHs or other hormones in lower insects.
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Affiliation(s)
- Xanthe Vafopoulou
- Department of Biology, York University, 4700 Keele St, Toronto, ON M3J 1P3, Canada
| | - Logan W Donaldson
- Department of Biology, York University, 4700 Keele St, Toronto, ON M3J 1P3, Canada
| | - Colin G H Steel
- Department of Biology, York University, 4700 Keele St, Toronto, ON M3J 1P3, Canada.
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12
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Robert C, Kerff F, Bouillenne F, Gavage M, Vandevenne M, Filée P, Matagne A. Structural analysis of the interaction between human cytokine BMP-2 and the antagonist Noggin reveals molecular details of cell chondrogenesis inhibition. J Biol Chem 2023; 299:102892. [PMID: 36642181 PMCID: PMC9929448 DOI: 10.1016/j.jbc.2023.102892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 01/04/2023] [Accepted: 01/06/2023] [Indexed: 01/14/2023] Open
Abstract
Bone morphogenetic proteins (BMPs) are secreted cytokines belonging to the transforming growth factor-β superfamily. New therapeutic approaches based on BMP activity, particularly for cartilage and bone repair, have sparked considerable interest; however, a lack of understanding of their interaction pathways and the side effects associated with their use as biopharmaceuticals have dampened initial enthusiasm. Here, we used BMP-2 as a model system to gain further insight into both the relationship between structure and function in BMPs and the principles that govern affinity for their cognate antagonist Noggin. We produced BMP-2 and Noggin as inclusion bodies in Escherichia coli and developed simple and efficient protocols for preparing pure and homogeneous (in terms of size distribution) solutions of the native dimeric forms of the two proteins. The identity and integrity of the proteins were confirmed using mass spectrometry. Additionally, several in vitro cell-based assays, including enzymatic measurements, RT-qPCR, and matrix staining, demonstrated their biological activity during cell chondrogenic and hypertrophic differentiation. Furthermore, we characterized the simple 1:1 noncovalent interaction between the two ligands (KDca. 0.4 nM) using bio-layer interferometry and solved the crystal structure of the complex using X-ray diffraction methods. We identified the residues and binding forces involved in the interaction between the two proteins. Finally, results obtained with the BMP-2 N102D mutant suggest that Noggin is remarkably flexible and able to accommodate major structural changes at the BMP-2 level. Altogether, our findings provide insights into BMP-2 activity and reveal the molecular details of its interaction with Noggin.
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Affiliation(s)
- Charly Robert
- Laboratory of Enzymology and Protein Folding, University of Liège, Liège, Belgium,Centre for Protein Engineering, InBioS Research Unit, University of Liège, Liège, Belgium
| | - Frédéric Kerff
- Centre for Protein Engineering, InBioS Research Unit, University of Liège, Liège, Belgium,Biological Macromolecule Crystallography, University of Liège, Liège, Belgium
| | - Fabrice Bouillenne
- Centre for Protein Engineering, InBioS Research Unit, University of Liège, Liège, Belgium
| | - Maxime Gavage
- Analytical Laboratory, CER Groupe, rue du Point du Jour, Marloie, Belgium
| | - Marylène Vandevenne
- Laboratory of Enzymology and Protein Folding, University of Liège, Liège, Belgium,Centre for Protein Engineering, InBioS Research Unit, University of Liège, Liège, Belgium
| | - Patrice Filée
- Laboratory of immuno-biology, CER Groupe, Novalis Science Park, Aye, Belgium
| | - André Matagne
- Laboratory of Enzymology and Protein Folding, University of Liège, Liège, Belgium; Centre for Protein Engineering, InBioS Research Unit, University of Liège, Liège, Belgium.
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13
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Yang CC, Masai H. Claspin is Required for Growth Recovery from Serum Starvation through Regulating the PI3K-PDK1-mTOR Pathway in Mammalian Cells. Mol Cell Biol 2023; 43:1-21. [PMID: 36720467 PMCID: PMC9936878 DOI: 10.1080/10985549.2022.2160598] [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] [Indexed: 02/01/2023] Open
Abstract
Claspin plays multiple important roles in regulation of DNA replication as a mediator for the cellular response to replication stress, an integral replication fork factor that facilitates replication fork progression and a factor that promotes initiation by recruiting Cdc7 kinase. Here, we report a novel role of Claspin in growth recovery from serum starvation, which requires the activation of PI3 kinase (PI3K)-PDK1-Akt-mTOR pathways. In the absence of Claspin, cells do not proceed into S phase and eventually die partially in a ROS- and p53-dependent manner. Claspin directly interacts with PI3K and mTOR, and is required for activation of PI3K-PDK1-mTOR and for that of mTOR downstream factors, p70S6K and 4EBP1, but not for p38 MAPK cascade during the recovery from serum starvation. PDK1 physically interacts with Claspin, notably with CKBD, in a manner dependent on phosphorylation of the latter protein, and is required for interaction of mTOR with Claspin. Thus, Claspin plays a novel role as a key regulator for nutrition-induced proliferation/survival signaling by activating the mTOR pathway. The results also suggest a possibility that Claspin may serve as a common mediator that receives signals from different PI3K-related kinases and transmit them to specific downstream kinases.
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Affiliation(s)
- Chi-Chun Yang
- Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Hisao Masai
- Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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14
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Tan J, Li Z, Liu L, Liu H, Xue J. IL‐17 in intervertebral disc degeneration: mechanistic insights and therapeutic implications. Cell Biol Int 2022; 46:535-547. [PMID: 35066966 DOI: 10.1002/cbin.11767] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/28/2021] [Accepted: 01/04/2022] [Indexed: 11/11/2022]
Affiliation(s)
- Jing‐Hua Tan
- The First Affiliated Hospital, Department of Spine Surgery, Hengyang Medical School, University of South ChinaHengyangHunan421001China
| | - Ze‐Peng Li
- The First Affiliated Hospital, Department of Spine Surgery, Hengyang Medical School, University of South ChinaHengyangHunan421001China
| | - Lu‐Lu Liu
- The First Affiliated Hospital, Department of Spine Surgery, Hengyang Medical School, University of South ChinaHengyangHunan421001China
| | - Hao Liu
- The First Affiliated Hospital, Department of Spine Surgery, Hengyang Medical School, University of South ChinaHengyangHunan421001China
| | - Jing‐Bo Xue
- The First Affiliated Hospital, Department of Spine Surgery, Hengyang Medical School, University of South ChinaHengyangHunan421001China
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15
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Roberts JH, Halper J. Growth Factor Roles in Soft Tissue Physiology and Pathophysiology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:139-159. [PMID: 34807418 DOI: 10.1007/978-3-030-80614-9_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Repair and healing of injured and diseased tendons has been traditionally fraught with apprehension and difficulties, and often led to rather unsatisfactory results. The burgeoning research field of growth factors has opened new venues for treatment of tendon disorders and injuries, and possibly for treatment of disorders of the aorta and major arteries as well. Several chapters in this volume elucidate the role of transforming growth factor β (TGFß) in pathogenesis of several heritable disorders affecting soft tissues, such as aorta, cardiac valves, and tendons and ligaments. Several members of the bone morphogenetic group either have been approved by the FDA for treatment of non-healing fractures or have been undergoing intensive clinical and experimental testing for use of healing bone fractures and tendon injuries. Because fibroblast growth factors (FGFs) are involved in embryonic development of tendons and muscles among other tissues and organs, the hope is that applied research on FGF biological effects will lead to the development of some new treatment strategies providing that we can control angiogenicity of these growth factors. The problem, or rather question, regarding practical use of imsulin-like growth factor I (IGF-I) in tendon repair is whether IGF-I acts independently or under the guidance of growth hormone. FGF2 or platelet-derived growth factor (PDGF) alone or in combination with IGF-I stimulates regeneration of periodontal ligament: a matter of importance in Marfan patients with periodontitis. In contrast, vascular endothelial growth factor (VEGF) appears to have rather deleterious effects on experimental tendon healing, perhaps because of its angiogenic activity and stimulation of matrix metalloproteinases-proteases whose increased expression has been documented in a variety of ruptured tendons. Other modalities, such as local administration of platelet-rich plasma (PRP) and/or of mesenchymal stem cells have been explored extensively in tendon healing. Though treatment with PRP and mesenchymal stem cells has met with some success in horses (who experience a lot of tendon injuries and other tendon problems), the use of PRP and mesenchymal stem cells in people has been more problematic and requires more studies before PRP and mesenchymal stem cells can become reliable tools in management of soft tissue injuries and disorders.
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Affiliation(s)
- Jennifer H Roberts
- Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA
| | - Jaroslava Halper
- Department of Pathology, College of Veterinary Medicine, and Department of Basic Sciences, AU/UGA Medical Partnership, The University of Georgia, Athens, GA, USA.
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16
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Greń BA, Dabrowski-Tumanski P, Niemyska W, Sulkowska JI. Lasso Proteins-Unifying Cysteine Knots and Miniproteins. Polymers (Basel) 2021; 13:3988. [PMID: 34833285 PMCID: PMC8621785 DOI: 10.3390/polym13223988] [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: 10/08/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 11/17/2022] Open
Abstract
Complex lasso proteins are a recently identified class of biological compounds that are present in considerable fraction of proteins with disulfide bridges. In this work, we look at complex lasso proteins as a generalization of well-known cysteine knots and miniproteins (lasso peptides). In particular, we show that complex lasso proteins with the same crucial topological features-cysteine knots and lasso peptides-are antimicrobial proteins, which suggests that they act as a molecular plug. Based on an analysis of the stability of the lasso piercing residue, we also introduce a method to determine which lasso motif is potentially functional. Using this method, we show that the lasso motif in antimicrobial proteins, as well in that in cytokines, is functionally relevant. We also study the evolution of lasso motifs, their conservation, and the usefulness of the lasso fingerprint, which extracts all topologically non-triviality concerning covalent loops. The work is completed by the presentation of extensive statistics on complex lasso proteins to analyze, in particular, the strange propensity for "negative" piercings. We also identify 21 previously unknown complex lasso proteins with an ester and a thioester bridge.
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Affiliation(s)
- Bartosz Ambroży Greń
- Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland; (B.A.G.); (P.D.-T.)
- Faculty of Physics, University of Warsaw, 02-093 Warsaw, Poland
| | | | - Wanda Niemyska
- Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, 02-097 Warsaw, Poland;
| | - Joanna Ida Sulkowska
- Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland; (B.A.G.); (P.D.-T.)
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17
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Sepúlveda V, Maurelia F, González M, Aguayo J, Caprile T. SCO-spondin, a giant matricellular protein that regulates cerebrospinal fluid activity. Fluids Barriers CNS 2021; 18:45. [PMID: 34600566 PMCID: PMC8487547 DOI: 10.1186/s12987-021-00277-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/11/2021] [Indexed: 12/28/2022] Open
Abstract
Cerebrospinal fluid is a clear fluid that occupies the ventricular and subarachnoid spaces within and around the brain and spinal cord. Cerebrospinal fluid is a dynamic signaling milieu that transports nutrients, waste materials and neuroactive substances that are crucial for the development, homeostasis and functionality of the central nervous system. The mechanisms that enable cerebrospinal fluid to simultaneously exert these homeostatic/dynamic functions are not fully understood. SCO-spondin is a large glycoprotein secreted since the early stages of development into the cerebrospinal fluid. Its domain architecture resembles a combination of a matricellular protein and the ligand-binding region of LDL receptor family. The matricellular proteins are a group of extracellular proteins with the capacity to interact with different molecules, such as growth factors, cytokines and cellular receptors; enabling the integration of information to modulate various physiological and pathological processes. In the same way, the LDL receptor family interacts with many ligands, including β-amyloid peptide and different growth factors. The domains similarity suggests that SCO-spondin is a matricellular protein enabled to bind, modulate, and transport different cerebrospinal fluid molecules. SCO-spondin can be found soluble or polymerized into a dynamic threadlike structure called the Reissner fiber, which extends from the diencephalon to the caudal tip of the spinal cord. Reissner fiber continuously moves caudally as new SCO-spondin molecules are added at the cephalic end and are disaggregated at the caudal end. This movement, like a conveyor belt, allows the transport of the bound molecules, thereby increasing their lifespan and action radius. The binding of SCO-spondin to some relevant molecules has already been reported; however, in this review we suggest more than 30 possible binding partners, including peptide β-amyloid and several growth factors. This new perspective characterizes SCO-spondin as a regulator of cerebrospinal fluid activity, explaining its high evolutionary conservation, its apparent multifunctionality, and the lethality or severe malformations, such as hydrocephalus and curved body axis, of knockout embryos. Understanding the regulation and identifying binding partners of SCO-spondin are crucial for better comprehension of cerebrospinal fluid physiology.
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Affiliation(s)
- Vania Sepúlveda
- Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Felipe Maurelia
- Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Maryori González
- Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Jaime Aguayo
- Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Teresa Caprile
- Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
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18
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Janjanam J, Pano G, Wang R, Minden-Birkenmaier BA, Breeze-Jones H, Baker E, Garcin C, Clayton G, Shirinifard A, Zaske AM, Finkelstein D, Labelle M. Matricellular protein WISP2 is an endogenous inhibitor of collagen linearization and cancer metastasis. Cancer Res 2021; 81:5666-5677. [PMID: 34385183 DOI: 10.1158/0008-5472.can-20-3982] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 07/06/2021] [Accepted: 08/11/2021] [Indexed: 11/16/2022]
Abstract
Collagen remodeling contributes to many physiological and pathological processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that WISP2 expression is lower in most solid tumors, in comparison to normal tissues. Consequently, genetic or pharmacological restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis in vivo in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2:WISP1 ratio.
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Affiliation(s)
| | - Glendin Pano
- Developmental Neurobiology, St. Jude Children's Research Hospital
| | - Ruishan Wang
- Developmental Neurobiology, St. Jude Children's Research Hospital
| | | | | | - Eleanor Baker
- Developmental Neurobiology, St. Jude Children's Research Hospital
| | - Cecile Garcin
- Developmental Neurobiology, St. Jude Children's Research Hospital
| | - Georgia Clayton
- Developmental Neurobiology, St. Jude Children's Research Hospital
| | | | - Ana Maria Zaske
- Department of Internal Medicine, UTHealth - The University of Texas Health Science Center at Houston
| | | | - Myriam Labelle
- Developmental Neurobiology, St. Jude Children's Research Hospital
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19
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Correns A, Zimmermann LMA, Baldock C, Sengle G. BMP antagonists in tissue development and disease. Matrix Biol Plus 2021; 11:100071. [PMID: 34435185 PMCID: PMC8377005 DOI: 10.1016/j.mbplus.2021.100071] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/04/2021] [Accepted: 06/06/2021] [Indexed: 12/12/2022] Open
Abstract
Bone morphogenic proteins (BMPs) are important growth regulators in embryogenesis and postnatal homeostasis. Their tight regulation is crucial for successful embryonic development as well as tissue homeostasis in the adult organism. BMP inhibition by natural extracellular biologic antagonists represents the most intensively studied mechanistic concept of BMP growth factor regulation. It was shown to be critical for numerous developmental programs, including germ layer specification and spatiotemporal gradients required for the establishment of the dorsal-ventral axis and organ formation. The importance of BMP antagonists for extracellular matrix homeostasis is illustrated by the numerous human connective tissue disorders caused by their mutational inactivation. Here, we will focus on the known functional interactions targeting BMP antagonists to the ECM and discuss how these interactions influence BMP antagonist activity. Moreover, we will provide an overview about the current concepts and investigated molecular mechanisms modulating BMP inhibitor function in the context of development and disease.
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Key Words
- ALK3, anaplastic lymphoma kinase 3
- ATF2, activating transcription factor 2
- ActR, activin receptor
- BDB2, brachydactyly type B2
- BISC, BMP-induced signalling complex
- BMP antagonists
- BMPER, BMP binding endothelial regulator
- BMPs, bone morphogenetic proteins
- Bone morphogenetic protein (BMP)
- CAN, cerberus and DAN
- CDD, craniodiaphyseal dysplasia
- CHRD domain, chordin specific domain
- CUB domain, for complement C1r/C1s, Uegf, Bmp1 domain
- Connective tissue disorder
- Cv2, crossveinless-2
- DAN, differential screening selected gene aberrative in neuroblastoma
- DSD, diaphanospondylodysostosis
- Dpp, decapentaplegic
- ECM, extracellular matrix
- ERK, extracellular signal-regulated kinases
- Extracellular matrix (ECM)
- FMF, fibrillin microfibrils
- HS, heparan sulphate
- HSPGs, heparan sulphate proteoglycans
- MAPKs, mitogen-activated protein kinases
- MGC1, megalocornea 1
- PI3K, phosphoinositide 3-kinase
- PRDC, protein related to DAN and Cerberus
- SOST, sclerostin
- SYNS1, multiple synostoses syndrome 1
- Scw, screw
- Sog, short gastrulation
- TCC, tarsal-carpal coalition syndrome
- TGF-β, transforming growth factor- β
- Tld, tolloid
- Tsg, twisted gastrulation
- VBCH, Van Buchem disease
- Xlr/Tll, xolloid-related metalloprotease
- vWC, von Willebrand factor type C
- vWD, von Willebrand factor type D
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Affiliation(s)
- Annkatrin Correns
- Department of Paediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Center for Biochemistry, Faculty of Medicine, University Hospital of Cologne, Joseph-Stelzmann-Str. 52, 50931 Cologne, Germany
| | - Laura-Marie A. Zimmermann
- Department of Paediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Center for Biochemistry, Faculty of Medicine, University Hospital of Cologne, Joseph-Stelzmann-Str. 52, 50931 Cologne, Germany
| | - Clair Baldock
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, B.3016 Michael Smith Building, Oxford Road, M13 9PT, Manchester, United Kingdom
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Michael Smith Building, M13 9PT, Manchester, UK
| | - Gerhard Sengle
- Department of Paediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Center for Biochemistry, Faculty of Medicine, University Hospital of Cologne, Joseph-Stelzmann-Str. 52, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 21, 50931 Cologne, Germany
- Cologne Centre for Musculoskeletal Biomechanics (CCMB), Joseph-Stelzmann-Str. 9, 50931 Cologne, Germany
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20
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Hayes-Ryan D, O'Donoghue K, McCarthy C, Totorika A, Meaney S. A comparative study of two immunoassays of maternal placental growth factor. Scandinavian Journal of Clinical and Laboratory Investigation 2021; 81:167-172. [PMID: 33821745 DOI: 10.1080/00365513.2021.1908589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Circulating maternal levels of placental growth factor correlates well with placental function and numerous studies advocate its role to help rule-out preterm pre-eclampsia. A number of automated immunoassay platforms to quantify placental growth factors are currently available. The aim of this study was to highlight the importance of developing and validating appropriate reference ranges and clinical cut-offs for immunoassays, by comparing the results obtained from two different immunoassays of placental growth factor; the Quantikine® ELISA and the automated Triage® test. This was a secondary subgroup analysis of samples collected as part of a prospective cross-sectional study of placental growth factors in twin pregnancy. Consenting pregnant women with a twin pregnancy, across a variety of gestations, had a single blood sample taken at a one-time point only during their pregnancy. The plasma was initially biobanked and then later analysed in batches using both immunoassays. Although the placental growth factor values of the two immunoassays correlated well (r = 0.88, n = 178, p < .001), the actual results obtained were significantly different (mean difference 238.1 pg/ml). Poor concordance between the two immunoassays was also present, with the Triage® test recording 36 cases as <100 pg/ml whereas the Quantikine® ELISA identified only 4 as <100 pg/ml. Biomarker levels may vary significantly between different immunoassay platforms, highlighting the importance of developing validated clinical cut-offs for any automated immunoassay before its clinical application. These differences need to be understood to facilitate clinical utility given that placental growth factor testing is likely to be introduced into widespread clinical practice.
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Affiliation(s)
- Deirdre Hayes-Ryan
- The Irish Centre for Maternal and Child Health Research, (INFANT), Cork, Ireland.,Cork University Maternity Hospital (CUMH), Ireland
| | - Keelin O'Donoghue
- The Irish Centre for Maternal and Child Health Research, (INFANT), Cork, Ireland.,Cork University Maternity Hospital (CUMH), Ireland
| | - Cathal McCarthy
- The Irish Centre for Maternal and Child Health Research, (INFANT), Cork, Ireland.,Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - Ainhoa Totorika
- The Irish Centre for Maternal and Child Health Research, (INFANT), Cork, Ireland
| | - Sarah Meaney
- National Perinatal Epidemiology Centre, University College Cork, Cork, Ireland
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21
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Sun K, Guo J, Yao X, Guo Z, Guo F. Growth differentiation factor 5 in cartilage and osteoarthritis: A possible therapeutic candidate. Cell Prolif 2021; 54:e12998. [PMID: 33522652 PMCID: PMC7941218 DOI: 10.1111/cpr.12998] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Growth differentiation factor 5 (GDF-5) is essential for cartilage development and homeostasis. The expression and function of GDF-5 are highly associated with the pathogenesis of osteoarthritis (OA). OA, characterized by progressive degeneration of joint, particularly in cartilage, causes severe social burden. However, there is no effective approach to reverse the progression of this disease. Over the past decades, extensive studies have demonstrated the protective effects of GDF-5 against cartilage degeneration and defects. Here, we summarize the current literature describing the role of GDF-5 in development of cartilage and joints, and the association between the GDF-5 gene polymorphisms and OA susceptibility. We also shed light on the protective effects of GDF-5 against OA in terms of direct GDF-5 supplementation and modulation of the GDF-5-related signalling. Finally, we discuss the current limitations in the application of GDF-5 for the clinical treatment of OA. This review provides a comprehensive insight into the role of GDF-5 in cartilage and emphasizes GDF-5 as a potential therapeutic candidate in OA.
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Affiliation(s)
- Kai Sun
- Department of OrthopedicsTongji Medical CollegeTongji HospitalHuazhong University of Science and TechnologyWuhanChina
| | - Jiachao Guo
- Department of OrthopedicsTongji Medical CollegeTongji HospitalHuazhong University of Science and TechnologyWuhanChina
| | - Xudong Yao
- Department of OrthopedicsTongji Medical CollegeTongji HospitalHuazhong University of Science and TechnologyWuhanChina
| | - Zhou Guo
- Department of OrthopedicsTongji Medical CollegeTongji HospitalHuazhong University of Science and TechnologyWuhanChina
| | - Fengjing Guo
- Department of OrthopedicsTongji Medical CollegeTongji HospitalHuazhong University of Science and TechnologyWuhanChina
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22
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Retzl B, Hellinger R, Muratspahić E, Pinto MEF, Bolzani VS, Gruber CW. Discovery of a Beetroot Protease Inhibitor to Identify and Classify Plant-Derived Cystine Knot Peptides. JOURNAL OF NATURAL PRODUCTS 2020; 83:3305-3314. [PMID: 33118348 PMCID: PMC7705960 DOI: 10.1021/acs.jnatprod.0c00648] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Indexed: 05/04/2023]
Abstract
Plant peptide protease inhibitors are important molecules in seed storage metabolism and to fight insect pests. Commonly they contain multiple disulfide bonds and are exceptionally stable molecules. In this study, a novel peptide protease inhibitor from beetroot (Beta vulgaris) termed bevuTI-I was isolated, and its primary structure was determined via mass spectrometry-based amino acid sequencing. By sequence homology analysis a few peptides with high similarity to bevuTI-I, also known as the Mirabilis jalapa trypsin inhibitor subfamily of knottin-type protease inhibitors, were discovered. Hence, we assessed bevuTI-I for inhibitory activity toward trypsin (IC50 = 471 nM) and human prolyl oligopeptidase (IC50 = 11 μM), which is an emerging drug target for neurodegenerative and inflammatory disorders. Interestingly, using a customized bioinformatics approach, bevuTI-I was found to be the missing link to annotate 243 novel sequences of M. jalapa trypsin inhibitor-like peptides. According to their phylogenetic distribution they appear to be common in several plant families. Therefore, the presented approach and our results may help to discover and classify other plant-derived cystine knot peptides, a class of plant molecules that play important functions in plant physiology and are currently being explored as lead molecules and scaffolds in drug development.
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Affiliation(s)
- Bernhard Retzl
- Center
for Physiology and Pharmacology, Medical
University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Roland Hellinger
- Center
for Physiology and Pharmacology, Medical
University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Edin Muratspahić
- Center
for Physiology and Pharmacology, Medical
University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Meri E. F. Pinto
- Center
for Physiology and Pharmacology, Medical
University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
- Institute
of Chemistry, São Paulo State University-UNESP, 14800-060, Araraquara, SP, Brazil
| | - Vanderlan S. Bolzani
- Institute
of Chemistry, São Paulo State University-UNESP, 14800-060, Araraquara, SP, Brazil
| | - Christian W. Gruber
- Center
for Physiology and Pharmacology, Medical
University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
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23
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Mezei M, Baliram R, Ali MR, Zaidi M, Davies TF, Latif R. The Human TSHβ Subunit Proteins and Their Binding Sites on the TSH Receptor Using Molecular Dynamics Simulation. Endocrinology 2020; 161:5879754. [PMID: 32738139 PMCID: PMC7447003 DOI: 10.1210/endocr/bqaa125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/30/2020] [Indexed: 12/18/2022]
Abstract
To gain further insight into the binding of the normal and variant human TSHβ subunits (TSHβ and TSHβv), we modeled the 2 monomeric proteins and studied their interaction with the TSH receptor ectodomain (TSHR-ECD) using molecular dynamics simulation Furthermore, analyzed their bioactivity in vitro using recombinant proteins to confirm that such binding was physiologically relevant. Examining the interaction of TSHβ and TSHβv with the TSHR-ECD model using molecular dynamic simulation revealed strong binding of these proteins to the receptor ECD. The specificity of TSHβ and TSHβv binding to the TSHR-ECD was examined by analyzing the hydrogen-bonding residues of these subunits to the FSH receptor ECD, indicating the inability of these molecules to bind to the FSH receptors. Furthermore, the modelling suggests that TSHβ and TSHβv proteins clasped the concave surface of the leucine rich region of the TSHR ECD in a similar way to the native TSH using dynamic hydrogen bonding. These mutually exclusive stable interactions between the subunits and ECD residues included some high-affinity contact sites corresponding to binding models of native TSH. Furthermore, we cloned TSHβ and TSHβv proteins using the entire coding ORF and purified the flag-tagged proteins. The expressed TSHβ subunit proteins retained bioactivity both in a coculture system as well as with immune-purified proteins. In summary, we showed that such interactions can result in a functional outcome and may exert physiological or pathophysiological effects in immune cells.
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Affiliation(s)
- Mihaly Mezei
- Department of Pharmacological Sciences, New York, New York
- Correspondence: Mihaly Mezei, Department of Pharmacological Sciences, Icahn school of Medicine, Ine Gustave L Levy PL, New York NY 10029. E-mail:
| | - Ramkumarie Baliram
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- James J. Peters VA Medical Center, New York, New York
| | - M Rejwan Ali
- Department of Pharmacological Sciences, New York, New York
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Mone Zaidi
- Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Terry F Davies
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- James J. Peters VA Medical Center, New York, New York
| | - Rauf Latif
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- James J. Peters VA Medical Center, New York, New York
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24
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Méndez-Maldonado K, Vega-López GA, Aybar MJ, Velasco I. Neurogenesis From Neural Crest Cells: Molecular Mechanisms in the Formation of Cranial Nerves and Ganglia. Front Cell Dev Biol 2020; 8:635. [PMID: 32850790 PMCID: PMC7427511 DOI: 10.3389/fcell.2020.00635] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 06/24/2020] [Indexed: 12/15/2022] Open
Abstract
The neural crest (NC) is a transient multipotent cell population that originates in the dorsal neural tube. Cells of the NC are highly migratory, as they travel considerable distances through the body to reach their final sites. Derivatives of the NC are neurons and glia of the peripheral nervous system (PNS) and the enteric nervous system as well as non-neural cells. Different signaling pathways triggered by Bone Morphogenetic Proteins (BMPs), Fibroblast Growth Factors (FGFs), Wnt proteins, Notch ligands, retinoic acid (RA), and Receptor Tyrosine Kinases (RTKs) participate in the processes of induction, specification, cell migration and neural differentiation of the NC. A specific set of signaling pathways and transcription factors are initially expressed in the neural plate border and then in the NC cell precursors to the formation of cranial nerves. The molecular mechanisms of control during embryonic development have been gradually elucidated, pointing to an important role of transcriptional regulators when neural differentiation occurs. However, some of these proteins have an important participation in malformations of the cranial portion and their mutation results in aberrant neurogenesis. This review aims to give an overview of the role of cell signaling and of the function of transcription factors involved in the specification of ganglia precursors and neurogenesis to form the NC-derived cranial nerves during organogenesis.
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Affiliation(s)
- Karla Méndez-Maldonado
- Instituto de Fisiología Celular - Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.,Departamento de Fisiología y Farmacología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Guillermo A Vega-López
- Instituto Superior de Investigaciones Biológicas (INSIBIO, CONICET-UNT), San Miguel de Tucumán, Argentina.,Instituto de Biología "Dr. Francisco D. Barbieri", Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Miguel de Tucumán, Argentina
| | - Manuel J Aybar
- Instituto Superior de Investigaciones Biológicas (INSIBIO, CONICET-UNT), San Miguel de Tucumán, Argentina.,Instituto de Biología "Dr. Francisco D. Barbieri", Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Miguel de Tucumán, Argentina
| | - Iván Velasco
- Instituto de Fisiología Celular - Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.,Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Ciudad de México, Mexico
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25
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Rossetti R, Ferrari I, Bestetti I, Moleri S, Brancati F, Petrone L, Finelli P, Persani L. Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency. Hum Mutat 2020; 41:983-997. [DOI: 10.1002/humu.23988] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 01/09/2020] [Accepted: 01/16/2020] [Indexed: 11/08/2022]
Affiliation(s)
- Raffaella Rossetti
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic ResearchIRCCS Istituto Auxologico ItalianoMilan Italy
| | - Ilaria Ferrari
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic ResearchIRCCS Istituto Auxologico ItalianoMilan Italy
| | - Ilaria Bestetti
- Lab of Medical Cytogenetics and Molecular GeneticsIstituto Auxologico Italiano, IRCCSMilan Italy
- Department of Medical Biotechnology and Translational MedicineUniversity of MilanMilan Italy
| | - Silvia Moleri
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic ResearchIRCCS Istituto Auxologico ItalianoMilan Italy
| | - Francesco Brancati
- Department of Life, Health and Environmental SciencesUniversity of L'AquilaL'Aquila Italy
- Laboratory of Molecular and Cell BiologyIstituto Dermopatico dell'Immacolata (IDI) IRCCSRome Italy
| | - Luisa Petrone
- Dipartimento Medico‐Geriatico, EndocrinologiaAzienda ospedaliero‐Universitaria CareggiFirenze Italy
| | - Palma Finelli
- Lab of Medical Cytogenetics and Molecular GeneticsIstituto Auxologico Italiano, IRCCSMilan Italy
- Department of Medical Biotechnology and Translational MedicineUniversity of MilanMilan Italy
| | - Luca Persani
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic ResearchIRCCS Istituto Auxologico ItalianoMilan Italy
- Department of Clinical Sciences and Community HealthUniversity of MilanMilan Italy
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26
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Larson SB, McPherson A. The crystal structure of the β subunit of luteinizing hormone and a model for the intact hormone. Curr Res Struct Biol 2019; 1:1-5. [PMID: 34235462 PMCID: PMC8244496 DOI: 10.1016/j.crstbi.2019.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/22/2019] [Accepted: 07/31/2019] [Indexed: 11/24/2022] Open
Abstract
The β subunit of bovine luteinizing hormone (LH) was crystallized and its structure solved to 3.15 Å resolution by molecular replacement using human chorionic gonadotropin (hCG) β subunit as search model. The asymmetric unit contains two copies of the β subunit that are related by a non-crystallographic symmetry (NCS) two-fold axis, both copies of which contain proteolytic cleavages after amino acid 100. It is noteworthy that the oligosaccharide moieties covalently attached at asparagine 13 were particularly pronounced in the electron density, allowing seven sugar residues to be defined. The α subunit of LH, which is common to all glycosylated gonadotropin hormones, was placed by superposition of hCG on the LH beta subunits, thereby yielding a model for the intact hormone.
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Affiliation(s)
- Steven B. Larson
- Dept. Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Alexander McPherson
- Dept. Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
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27
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Spider Knottin Pharmacology at Voltage-Gated Sodium Channels and Their Potential to Modulate Pain Pathways. Toxins (Basel) 2019; 11:toxins11110626. [PMID: 31671792 PMCID: PMC6891507 DOI: 10.3390/toxins11110626] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/24/2019] [Accepted: 10/24/2019] [Indexed: 12/15/2022] Open
Abstract
Voltage-gated sodium channels (NaVs) are a key determinant of neuronal signalling. Neurotoxins from diverse taxa that selectively activate or inhibit NaV channels have helped unravel the role of NaV channels in diseases, including chronic pain. Spider venoms contain the most diverse array of inhibitor cystine knot (ICK) toxins (knottins). This review provides an overview on how spider knottins modulate NaV channels and describes the structural features and molecular determinants that influence their affinity and subtype selectivity. Genetic and functional evidence support a major involvement of NaV subtypes in various chronic pain conditions. The exquisite inhibitory properties of spider knottins over key NaV subtypes make them the best lead molecules for the development of novel analgesics to treat chronic pain.
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28
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Kostareva OS, Gabdulkhakov AG, Kolyadenko IA, Garber MB, Tishchenko SV. Interleukin-17: Functional and Structural Features, Application as a Therapeutic Target. BIOCHEMISTRY (MOSCOW) 2019; 84:S193-S205. [PMID: 31213202 DOI: 10.1134/s0006297919140116] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cytokines of the IL-17 family play a key role in the host organism defense against bacterial and fungal infections. At the same time, upregulated synthesis of IL-17 cytokines is associated with immunoinflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and others. The members of this family are important therapeutic targets in the treatment of various human chronic inflammatory disorders. Elucidation of signaling pathways involving IL-17 family proteins and analysis of the structure of cytokine complexes with specific antibodies, inhibitors, and receptors are essential for the development of new drugs for the therapy of immunoinflammatory rheumatic diseases.
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Affiliation(s)
- O S Kostareva
- Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
| | - A G Gabdulkhakov
- Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - I A Kolyadenko
- Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - M B Garber
- Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - S V Tishchenko
- Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
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29
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Asymmetric paralog evolution between the "cryptic" gene Bmp16 and its well-studied sister genes Bmp2 and Bmp4. Sci Rep 2019; 9:3136. [PMID: 30816280 PMCID: PMC6395752 DOI: 10.1038/s41598-019-40055-1] [Citation(s) in RCA: 236] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 02/07/2019] [Indexed: 12/05/2022] Open
Abstract
The vertebrate gene repertoire is characterized by “cryptic” genes whose identification has been hampered by their absence from the genomes of well-studied species. One example is the Bmp16 gene, a paralog of the developmental key genes Bmp2 and -4. We focus on the Bmp2/4/16 group of genes to study the evolutionary dynamics following gen(om)e duplications with special emphasis on the poorly studied Bmp16 gene. We reveal the presence of Bmp16 in chondrichthyans in addition to previously reported teleost fishes and reptiles. Using comprehensive, vertebrate-wide gene sampling, our phylogenetic analysis complemented with synteny analyses suggests that Bmp2, -4 and -16 are remnants of a gene quartet that originated during the two rounds of whole-genome duplication (2R-WGD) early in vertebrate evolution. We confirm that Bmp16 genes were lost independently in at least three lineages (mammals, archelosaurs and amphibians) and report that they have elevated rates of sequence evolution. This finding agrees with their more “flexible” deployment during development; while Bmp16 has limited embryonic expression domains in the cloudy catshark, it is broadly expressed in the green anole lizard. Our study illustrates the dynamics of gene family evolution by integrating insights from sequence diversification, gene repertoire changes, and shuffling of expression domains.
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30
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Analysis of novel domain-specific mutations in the zebrafish ndr2/cyclops gene generated using CRISPR-Cas9 RNPs. J Genet 2018. [DOI: 10.1007/s12041-018-1033-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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31
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The Interleukin-17 Family of Cytokines in Breast Cancer. Int J Mol Sci 2018; 19:ijms19123880. [PMID: 30518157 PMCID: PMC6321268 DOI: 10.3390/ijms19123880] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/26/2018] [Accepted: 11/28/2018] [Indexed: 02/07/2023] Open
Abstract
Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and mammalian target of rapamycin (mTOR) inhibitors have recently proved their efficiency in hormonal receptor expressing BC. Checkpoint proteins inhibition is being evaluated in phase 3 studies. Since inflammation is constantly present in cancers, research teams have focused their attention on the interleukin-17 (IL-17) family of proinflammatory cytokines. Preclinical experiments have reported both pro and antitumor effects depending on the conditions. In the present article, we review the accumulating evidences about the roles of IL-17 in BC and discuss whether this family of cytokines could be a new target in anticancer treatments.
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32
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Smani T, Gómez LJ, Regodon S, Woodard GE, Siegfried G, Khatib AM, Rosado JA. TRP Channels in Angiogenesis and Other Endothelial Functions. Front Physiol 2018; 9:1731. [PMID: 30559679 PMCID: PMC6287032 DOI: 10.3389/fphys.2018.01731] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 11/16/2018] [Indexed: 12/19/2022] Open
Abstract
Angiogenesis is the growth of blood vessels mediated by proliferation, migration, and spatial organization of endothelial cells. This mechanism is regulated by a balance between stimulatory and inhibitory factors. Proangiogenic factors include a variety of VEGF family members, while thrombospondin and endostatin, among others, have been reported as suppressors of angiogenesis. Transient receptor potential (TRP) channels belong to a superfamily of cation-permeable channels that play a relevant role in a number of cellular functions mostly derived from their influence in intracellular Ca2+ homeostasis. Endothelial cells express a variety of TRP channels, including members of the TRPC, TRPV, TRPP, TRPA, and TRPM families, which play a relevant role in a number of functions, including endothelium-induced vasodilation, vascular permeability as well as sensing hemodynamic and chemical changes. Furthermore, TRP channels have been reported to play an important role in angiogenesis. This review summarizes the current knowledge and limitations concerning the involvement of particular TRP channels in growth factor-induced angiogenesis.
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Affiliation(s)
- Tarik Smani
- Department of Medical Physiology and Biophysic, Institute of Biomedicine of Seville, University of Seville, Sevilla, Spain.,CIBERCV, Madrid, Spain
| | - Luis J Gómez
- Department of Animal Medicine, University of Extremadura, Cáceres, Spain
| | - Sergio Regodon
- Department of Animal Medicine, University of Extremadura, Cáceres, Spain
| | - Geoffrey E Woodard
- Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | | | | | - Juan A Rosado
- Cell Physiology Research Group, Department of Physiology, University of Extremadura, Cáceres, Spain
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33
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Turner AN, Andersen RS, Bookout IE, Brashear LN, Davis JC, Gahan DM, Davis JC, Gotham JP, Hijaz BA, Kaushik AS, Mcgill JB, Miller VL, Moseley ZP, Nowell CL, Patel RK, Rodgers MC, Patel RK, Shihab YA, Walker AP, Glover SR, Foster SD, Challa AK. Analysis of novel domain-specific mutations in the zebrafish ndr2/ cyclops gene generated using CRISPR-Cas9 RNPs. J Genet 2018. [PMID: 30555080 DOI: 10.1101/277715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Nodal-related protein (ndr2) is amember of the transforming growth factor type β superfamily of factors and is required for ventral midline patterning of the embryonic central nervous system in zebrafish. In humans, mutations in the gene encoding nodal cause holoprosencephaly and heterotaxy. Mutations in the ndr2 gene in the zebrafish (Danio rerio) lead to similar phenotypes, including loss of the medial floor plate, severe deficits in ventral forebrain development and cyclopia. Alleles of the ndr2 gene have been useful in studying patterning of ventral structures of the central nervous system. Fifteen different ndr2 alleles have been reported in zebrafish, of which eight were generated using chemical mutagenesis, four were radiation-induced and the remaining alleles were obtained via random insertion, gene targeting (TALEN) or unknown methods. Therefore, most mutation sites were random and could not be predicted a priori. Using the CRISPR-Cas9 system from Streptococcus pyogenes, we targeted distinct regions in all three exons of zebrafish ndr2 and observed cyclopia in the injected (G0) embryos.We show that the use of sgRNA-Cas9 ribonucleoprotein (RNP) complexes can cause penetrant cyclopic phenotypes in injected (G0) embryos. Targeted polymerase chain reaction amplicon analysis using Sanger sequencing showed that most of the alleles had small indels resulting in frameshifts. The sequence information correlates with the loss of ndr2 activity. In this study, we validate multiple CRISPR targets using an in vitro nuclease assay and in vivo analysis using embryos. We describe one specific mutant allele resulting in the loss of conserved terminal cysteine-coding sequences. This study is another demonstration of the utility of the CRISPR-Cas9 system in generating domain-specific mutations and provides further insights into the structure-function of the ndr2 gene.
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Affiliation(s)
- Ashley N Turner
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Xu YR, Wang GY, Zhou YC, Yang WX. The characterization and potential roles of bone morphogenetic protein 7 during spermatogenesis in Chinese mitten crab Eriocheir sinensis. Gene 2018; 673:119-129. [PMID: 29890312 DOI: 10.1016/j.gene.2018.06.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 05/31/2018] [Accepted: 06/07/2018] [Indexed: 01/12/2023]
Abstract
Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-β superfamily, have been implicated in various biological and physiological processes, especially in the gonad development. However, scarce studies were focused on the roles of BMPs in the reproductive system of crustaceans. In this study, the whole gene encoding BMP7 protein was cloned and characterized firstly in Chinese mitten crab Eriocheir sinensis. The bioinformatics analysis of the deduced amino acid sequence showed that Es-BMP7 was composed of prodomain/latency-associated peptide and the TGF-β characteristic domain. The sequence conservation and phylogenetic analysis were also conducted. Quantitative real-time PCR was conducted indifferent tissues. The highest expression in testis indicated the potential role of BMP7 to male gonad development. Western blot results showed the different translational levels of BMP7 in different tissues. In-situ hybridization revealed that the expression of es-bmp7 signals presented in a bimodal manner: highest in spermatogonia, decreased in spermatocytes and stage I spermatids, disappeared in stage II spermatids, and showed up again in stage III spermatids and mature sperm. To further verify the potential roles during spermatogenesis, immunofluorescence was conducted and results showed the similar expression tendency with in situ hybridization. The protein signal was highest in the cytoplasm of spermatogonia, continued to decline in the cytoplasm of spermatocytes and the following stages, and weak signal was found in the mature sperm. Taken together, our results revealed that Es-BMP7 might play a part in testis development in Eriocheir sinensis, presumably by maintaining the self-renewal of spermatogonia and promoting the germ cell differentiation/meiotic mitosis, or facilitating the successful fertilization.
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Affiliation(s)
- Ya-Ru Xu
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Gao-Yuan Wang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yi-Chao Zhou
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wan-Xi Yang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
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35
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Apicella I, Cicatiello V, Acampora D, Tarallo V, De Falco S. Full Functional Knockout of Placental Growth Factor by Knockin with an Inactive Variant Able to Heterodimerize with VEGF-A. Cell Rep 2018; 23:3635-3646. [DOI: 10.1016/j.celrep.2018.05.067] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 04/17/2018] [Accepted: 05/18/2018] [Indexed: 12/18/2022] Open
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36
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Quaas B, Burmeister L, Li Z, Nimtz M, Hoffmann A, Rinas U. Properties of dimeric, disulfide-linked rhBMP-2 recovered from E. coli derived inclusion bodies by mild extraction or chaotropic solubilization and subsequent refolding. Process Biochem 2018. [DOI: 10.1016/j.procbio.2018.02.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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37
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Placental growth factor: A review of literature and future applications. Pregnancy Hypertens 2018; 14:260-264. [PMID: 29555222 DOI: 10.1016/j.preghy.2018.03.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 03/08/2018] [Accepted: 03/09/2018] [Indexed: 12/11/2022]
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38
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Emerging Roles for VEGF-D in Human Disease. Biomolecules 2018; 8:biom8010001. [PMID: 29300337 PMCID: PMC5871970 DOI: 10.3390/biom8010001] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/22/2017] [Accepted: 12/28/2017] [Indexed: 12/21/2022] Open
Abstract
Blood vessels and lymphatic vessels are located in many tissues and organs throughout the body, and play important roles in a wide variety of prevalent diseases in humans. Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that can promote the remodeling of blood vessels and lymphatics in development and disease. Recent fundamental and translational studies have provided insight into the molecular mechanisms by which VEGF-D exerts its effects in human disease. Hence this protein is now of interest as a therapeutic and/or diagnostic target, or as a potential therapeutic agent, in a diversity of indications in cardiovascular medicine, cancer and the devastating pulmonary condition lymphangioleiomyomatosis. This has led to clinical trial programs to assess the effect of targeting VEGF-D signaling pathways, or delivering VEGF-D, in angina, cancer and ocular indications. This review summarizes our understanding of VEGF-D signaling in human disease, which is largely based on animal disease models and clinicopathological studies, and provides information about the outcomes of recent clinical trials testing agonists or antagonists of VEGF-D signaling.
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39
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Tripathy M, Priyam M, Rai U. Repertoire of bone morphogenetic proteins and growth/differentiation factors in ovary of the Indian wall lizard (Hemidactylus flaviviridis) with emphasis on differential expression and gonadotropic regulation of bmp15 and gdf9. Gen Comp Endocrinol 2017; 253:13-24. [PMID: 28837789 DOI: 10.1016/j.ygcen.2017.08.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/28/2017] [Accepted: 08/14/2017] [Indexed: 11/23/2022]
Abstract
Analysis of ovarian transcriptome of Indian wall lizard demonstrates the existence of several bone morphogenetic proteins (bmp1, 2, 3, 3b, 7, 8, 15) and growth/differentiation factors (gdf5, 9) for the first time in reptilian ovary. The characterization of putative full-length/partial protein sequences of BMPs (BMP2, 3, 3b, 7, 15) and GDF9 showed high homology of their TGF-β domain with that of other vertebrates while BMP1 bore homology to zinc-dependent metalloprotease. Phylogenetic analyses showed clustering of BMPs and GDF9 from wall lizards with that of squamates lying in close proximity to chelonia, crocodilia and aves. This study also correlates the expression of ovarian bmp15 and gdf9 with folliculogenesis. Level of bmp15 dramatically increased with the onset of follicular growth in early recrudescence and attained peak during late recrudescence whereas gdf9 sharply decreased during recrudescence as compared to regression. Nonetheless, expression of these growth factors decreased appreciably with the formation of vitellogenic follicle during breeding phase. Ovarian expression of bmp15 and gdf9 appeared to be regulated by gonadotropin as bmp15 considerably increased while gdf9 decreased in parallel to follicular development after administration of 3 injections of FSH. Expression of both the growth factors declined with the prolongation of treatment that led to formation of early/late vitellogenic follicle. Our in vitro study revealed stimulatory effect of FSH on expression of bmp15 and gdf9 in early growing, previtellogenic and early vitellogenic follicles. In light of in vitro results, FSH-induced in vivo decline in gene expression seems to be due to some other FSH-induced factor.
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Affiliation(s)
- Mamta Tripathy
- Comparative Immunoendocrinology Laboratory, Department of Zoology, University of Delhi, Delhi 110007, India
| | - Manisha Priyam
- Comparative Immunoendocrinology Laboratory, Department of Zoology, University of Delhi, Delhi 110007, India
| | - Umesh Rai
- Comparative Immunoendocrinology Laboratory, Department of Zoology, University of Delhi, Delhi 110007, India.
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40
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Heath DA, Pitman JL, McNatty KP. Molecular forms of ruminant BMP15 and GDF9 and putative interactions with receptors. Reproduction 2017; 154:521-534. [PMID: 28733348 DOI: 10.1530/rep-17-0188] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 07/17/2017] [Accepted: 07/21/2017] [Indexed: 12/13/2022]
Abstract
Bone morphogenetic factor 15 (BMP15) and growth differentiation factor 9 (GDF9) are oocyte-secreted factors with demonstrable effects on ovarian follicular development and ovulation rate. However, the molecular forms of BMP15 and GDF9 produced by oocytes remain unclear. The aims herein, using Western blotting (WB) procedures with specific monoclonal antibodies (mabs), were to identify the molecular forms of BMP15 and GDF9 synthesised and secreted by isolated ovine (o) and bovine (b) oocytes in vitro The mabs were known to recognise the biological forms of BMP15 or GDF9 since they had previously been shown to inhibit their bioactivities in vitro and in vivo Using recombinant variants of oBMP15 and oGDF9, including a cysteine mutant form of oBMP15 (S356C) and a human (h) BMP15:GDF9 heterodimer (cumulin), it was established that the mabs were able to identify monomeric, dimeric, promature and higher-molecular-weight forms of BMP15 and GDF9 and cumulin (GDF9 mab only). After using non-reducing, reducing and reducing + cross-linking conditions, the major oocyte-secreted forms of o and b BMP15 and GDF9 were the cleaved and uncleaved monomeric forms of the promature proteins. There was no evidence for dimeric or heterodimeric forms of either mature BMP15 or GDF9. From in silico modelling studies using transforming growth factor beta (TGFB), activin or BMP crystal templates, and both present and previously published data, a model is proposed to illustrate how the monomeric forms of BMP15 and GDF9 may interact with their type II and type I cell-surface receptors to initiate the synergistic actions of these growth factors.
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Affiliation(s)
- Derek A Heath
- School of Biological SciencesVictoria University of Wellington, Wellington, New Zealand
| | - Janet L Pitman
- School of Biological SciencesVictoria University of Wellington, Wellington, New Zealand
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IL-17B: A new area of study in the IL-17 family. Mol Immunol 2017; 90:50-56. [PMID: 28704706 DOI: 10.1016/j.molimm.2017.07.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 06/11/2017] [Accepted: 07/01/2017] [Indexed: 01/21/2023]
Abstract
The interleukin (IL)-17 superfamily, a relatively new family of cytokines, consists of six ligands (from IL-17A to IL-17F), which bind to five receptor subtypes (from IL-17RA to IL-17RE) and induce downstream signaling. IL-17A, a prototype member of this family, has been reported to be involved in the pathogenesis of allergies, autoimmune diseases, allograft transplantations, and malignancies. Unlike IL-17A, which is mainly produced by T helper 17 cells, IL-17B is widely expressed in various tissues. Recently, the biological function of IL-17B in diseases, particularly tumors, has attracted the attention of researchers. We previously reported that the expression of IL-17RB increased in gastric cancer tissues and demonstrated that IL-17B/IL-17RB signaling plays a critical role in gastric tumor progression. However, studies on IL-17B are scant. In this review, we detail the structural characteristics, expression patterns, and biological activities of IL-17B and its potential role in the pathogenesis of diseases.
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42
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Ayerst BI, Merry CLR, Day AJ. The Good the Bad and the Ugly of Glycosaminoglycans in Tissue Engineering Applications. Pharmaceuticals (Basel) 2017; 10:E54. [PMID: 28608822 PMCID: PMC5490411 DOI: 10.3390/ph10020054] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 06/05/2017] [Accepted: 06/05/2017] [Indexed: 12/14/2022] Open
Abstract
High sulfation, low cost, and the status of heparin as an already FDA- and EMA- approved product, mean that its inclusion in tissue engineering (TE) strategies is becoming increasingly popular. However, the use of heparin may represent a naïve approach. This is because tissue formation is a highly orchestrated process, involving the temporal expression of numerous growth factors and complex signaling networks. While heparin may enhance the retention and activity of certain growth factors under particular conditions, its binding 'promiscuity' means that it may also inhibit other factors that, for example, play an important role in tissue maintenance and repair. Within this review we focus on articular cartilage, highlighting the complexities and highly regulated processes that are involved in its formation, and the challenges that exist in trying to effectively engineer this tissue. Here we discuss the opportunities that glycosaminoglycans (GAGs) may provide in advancing this important area of regenerative medicine, placing emphasis on the need to move away from the common use of heparin, and instead focus research towards the utility of specific GAG preparations that are able to modulate the activity of growth factors in a more controlled and defined manner, with less off-target effects.
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Affiliation(s)
- Bethanie I Ayerst
- Wellcome Trust Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative Medicine, School of Biology, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PL, UK.
| | - Catherine L R Merry
- Stem Cell Glycobiology Group, Wolfson Centre for Stem Cells, Tissue Engineering & Modelling (STEM), Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
| | - Anthony J Day
- Wellcome Trust Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative Medicine, School of Biology, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PL, UK.
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Richardson JS, Videau LL, Williams CJ, Richardson DC. Broad Analysis of Vicinal Disulfides: Occurrences, Conformations with Cis or with Trans Peptides, and Functional Roles Including Sugar Binding. J Mol Biol 2017; 429:1321-1335. [PMID: 28336403 DOI: 10.1016/j.jmb.2017.03.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 03/12/2017] [Accepted: 03/13/2017] [Indexed: 10/19/2022]
Abstract
Vicinal disulfides between sequence-adjacent cysteine residues are very rare and rather startling structural features which play a variety of functional roles. Typically discussed as an isolated curiosity, they have never received a general treatment covering both cis and trans forms. Enabled by the growing database of high-resolution structures, required deposition of diffraction data, and improved methods for discriminating reliable from dubious cases, we identify and describe distinct protein families with reliably genuine examples of cis or trans vicinal disulfides and discuss their conformations, conservation, and functions. No cis-trans interconversions and only one case of catalytic redox function are seen. Some vicinal disulfides are essential to large, functionally coupled motions, whereas most form the centers of tightly packed internal regions. Their most widespread biological role is providing a rigid hydrophobic contact surface under the undecorated side of a sugar or multiring ligand, contributing an important aspect of binding specificity.
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Affiliation(s)
- Jane S Richardson
- Department of Biochemistry, 3711 Duke University Medical Center, Durham, NC 27710, USA.
| | - Lizbeth L Videau
- Department of Biochemistry, 3711 Duke University Medical Center, Durham, NC 27710, USA
| | | | - David C Richardson
- Department of Biochemistry, 3711 Duke University Medical Center, Durham, NC 27710, USA
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Abstract
Long, flexible physical filaments are naturally tangled and knotted, from macroscopic string down to long-chain molecules. The existence of knotting in a filament naturally affects its configuration and properties, and may be very stable or disappear rapidly under manipulation and interaction. Knotting has been previously identified in protein backbone chains, for which these mechanical constraints are of fundamental importance to their molecular functionality, despite their being open curves in which the knots are not mathematically well defined; knotting can only be identified by closing the termini of the chain somehow. We introduce a new method for resolving knotting in open curves using virtual knots, which are a wider class of topological objects that do not require a classical closure and so naturally capture the topological ambiguity inherent in open curves. We describe the results of analysing proteins in the Protein Data Bank by this new scheme, recovering and extending previous knotting results, and identifying topological interest in some new cases. The statistics of virtual knots in protein chains are compared with those of open random walks and Hamiltonian subchains on cubic lattices, identifying a regime of open curves in which the virtual knotting description is likely to be important.
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Amarnath S, Stevens LM, Stein DS. Reconstitution of Torso signaling in cultured cells suggests a role for both Trunk and Torso-like in receptor activation. Development 2017; 144:677-686. [PMID: 28087630 DOI: 10.1242/dev.146076] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 12/30/2016] [Indexed: 12/15/2022]
Abstract
Formation of the Drosophila embryonic termini is controlled by the localized activation of the receptor tyrosine kinase Torso. Both Torso and Torso's presumed ligand, Trunk, are expressed uniformly in the early embryo. Polar activation of Torso requires Torso-like, which is expressed by follicle cells adjacent to the ends of the developing oocyte. We find that Torso expressed at high levels in cultured Drosophila cells is activated by individual application of Trunk, Torso-like or another known Torso ligand, Prothoracicotropic Hormone. In addition to assays of downstream signaling activity, Torso dimerization was detected using bimolecular fluorescence complementation. Trunk and Torso-like were active when co-transfected with Torso and when presented to Torso-expressing cells in conditioned medium. Trunk and Torso-like were also taken up from conditioned medium specifically by cells expressing Torso. At low levels of Torso, similar to those present in the embryo, Trunk and Torso-like alone were ineffective but acted synergistically to stimulate Torso signaling. Our results suggest that Torso interacts with both Trunk and Torso-like, which cooperate to mediate dimerization and activation of Torso at the ends of the Drosophila embryo.
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Affiliation(s)
- Smita Amarnath
- Department of Molecular Biosciences and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Patterson Labs 532, 2401 Speedway, Austin, TX 78712, USA
| | - Leslie M Stevens
- Department of Molecular Biosciences and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Patterson Labs 532, 2401 Speedway, Austin, TX 78712, USA
| | - David S Stein
- Department of Molecular Biosciences and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Patterson Labs 532, 2401 Speedway, Austin, TX 78712, USA
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Núñez Miguel R, Sanders J, Furmaniak J, Rees Smith B. Glycosylation pattern analysis of glycoprotein hormones and their receptors. J Mol Endocrinol 2017; 58:25-41. [PMID: 27875255 DOI: 10.1530/jme-16-0169] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 11/13/2016] [Indexed: 11/08/2022]
Abstract
We have studied glycosylation patterns in glycoprotein hormones (GPHs) and glycoprotein hormone receptor (GPHR) extracellular domains (ECD) from different species to identify areas not glycosylated that could be involved in intermolecular or intramolecular interactions. Comparative models of the structure of the TSHR ECD in complex with TSH and in complex with TSHR autoantibodies (M22, stimulating and K1-70, blocking) were obtained based on the crystal structures of the FSH-FSHR ECD, M22-TSHR leucine-rich repeat domain (LRD) and K1-70-TSHR LRD complexes. The glycosylation sites of the GPHRs and GPHs from all species studied were mapped on the model of the human TSH TSHR ECD complex. The areas on the surfaces of GPHs that are known to interact with their receptors are not glycosylated and two areas free from glycosylation, not involved in currently known interactions, have been identified. The concave faces of GPHRs leucine-rich repeats 3-7 are free from glycosylation, consistent with known interactions with the hormones. In addition, four other non-glycosylated areas have been identified, two located on the receptors' convex surfaces, one in the long loop of the hinge regions and one at the C-terminus of the extracellular domains. Experimental evidence suggests that the non-glycosylated areas identified on the hormones and receptors are likely to be involved in forming intramolecular or intermolecular interactions.
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47
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Allen CD, Chen MY, Trick AY, Le DT, Ferguson AL, Link AJ. Thermal Unthreading of the Lasso Peptides Astexin-2 and Astexin-3. ACS Chem Biol 2016; 11:3043-3051. [PMID: 27588549 DOI: 10.1021/acschembio.6b00588] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Lasso peptides are a class of knot-like polypeptides in which the C-terminal tail of the peptide threads through a ring formed by an isopeptide bond between the N-terminal amine group and a side chain carboxylic acid. The small size (∼20 amino acids) and simple topology of lasso peptides make them a good model system for studying the unthreading of entangled polypeptides, both with experiments and atomistic simulation. Here, we present an in-depth study of the thermal unthreading behavior of two lasso peptides astexin-2 and astexin-3. Quantitative kinetics and energetics of the unthreading process were determined for variants of these peptides using a series of chromatography and mass spectrometry experiments and biased molecular dynamics (MD) simulations. In addition, we show that the Tyr15Phe variant of astexin-3 unthreads via an unprecedented "tail pulling" mechanism. MD simulations on a model ring-thread system coupled with machine learning approaches also led to the discovery of physicochemical descriptors most important for peptide unthreading.
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Affiliation(s)
- Caitlin D. Allen
- Departments of Chemical and Biological Engineering and ‡Molecular Biology, Princeton University, Princeton, New Jersey 08544, United States
- Department of Materials
Science and Engineering and ∥Chemical and Biomolecular Engineering, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Maria Y. Chen
- Departments of Chemical and Biological Engineering and ‡Molecular Biology, Princeton University, Princeton, New Jersey 08544, United States
- Department of Materials
Science and Engineering and ∥Chemical and Biomolecular Engineering, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Alexander Y. Trick
- Departments of Chemical and Biological Engineering and ‡Molecular Biology, Princeton University, Princeton, New Jersey 08544, United States
- Department of Materials
Science and Engineering and ∥Chemical and Biomolecular Engineering, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Dan Thanh Le
- Departments of Chemical and Biological Engineering and ‡Molecular Biology, Princeton University, Princeton, New Jersey 08544, United States
- Department of Materials
Science and Engineering and ∥Chemical and Biomolecular Engineering, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Andrew L. Ferguson
- Departments of Chemical and Biological Engineering and ‡Molecular Biology, Princeton University, Princeton, New Jersey 08544, United States
- Department of Materials
Science and Engineering and ∥Chemical and Biomolecular Engineering, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
| | - A. James Link
- Departments of Chemical and Biological Engineering and ‡Molecular Biology, Princeton University, Princeton, New Jersey 08544, United States
- Department of Materials
Science and Engineering and ∥Chemical and Biomolecular Engineering, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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CILLER IM, PALANISAMY SKA, CILLER UA, MCFARLANE JR. Postnatal Expression of Bone Morphogenetic Proteins and Their Receptors in the Mouse Testis. Physiol Res 2016; 65:673-682. [DOI: 10.33549/physiolres.933193] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
TGF-β superfamily members including bone morphogenetic proteins (BMPs) and their receptors (BMPR-1A, -1B and -2) have been shown to be important for reproductive function in both males and females, while information on the role of BMPs in males is limited. Functional studies on select BMPs and BMP receptors have demonstrated vital roles for these proteins in somatic and germ cell proliferation, steroidogenesis and overall fertility. In order to gain insight into the importance of these genes during postnatal reproductive development in males, our study was undertaken to specify the distribution of BMP and BMPR mRNA in male reproductive and steroidogenic tissues and quantify these genes in the testis using the mouse as our model. We screened testis at two, four, six and eight weeks of age for the expression of ten BMPs and three BMP receptors using RT-qPCR. All three BMP receptor mRNAs – Bmpr1a, Bmpr1b and Bmpr2, and ten BMP mRNAs – Bmp2, Bmp3, Bmp3b, Bmp4, Bmp5, Bmp6, Bmp7, Bmp8a, Bmp8b and Bmp15 were expressed in mouse testis at all stages screened. Testicular expression of genes varied within age groups and at specific developmental stages. Our study establishes an extensive BMP system in mouse reproductive and steroidogenic tissues.
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Affiliation(s)
- I. M. CILLER
- Centre for Bioactive Discovery in Health and Ageing, School of Science and Technology, University of New England, Armidale, Australia
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The Discovery and Early Days of TGF-β: A Historical Perspective. Cold Spring Harb Perspect Biol 2016; 8:cshperspect.a021865. [PMID: 27328871 DOI: 10.1101/cshperspect.a021865] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Transforming growth factors (TGFs) were discovered as activities that were secreted by cancer cells, and later by normal cells, and had the ability to phenotypically and reversibly transform immortalized fibroblasts. TGF-β distinguished itself from TGF-α because it did not bind to the same epidermal growth factor (EGF) receptor as TGF-α and, therefore, acted through different cell-surface receptors and signaling mediators. This review summarizes the discovery of TGF-β, the early developments in its molecular and biological characterization with its many biological activities in different cell and tissue contexts and its roles in disease, the realization that there is a family of secreted TGF-β-related proteins with many differentiation functions in development and activities in normal cell and tissue physiology, and the subsequent identification and characterization of the receptors and effectors that mediate TGF-β family signaling responses.
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50
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Li FF, Deng X, Zhou J, Yan P, Zhao EY, Liu SL. Characterization of human bone morphogenetic protein gene variants for possible roles in congenital heart disease. Mol Med Rep 2016; 14:1459-64. [PMID: 27357418 PMCID: PMC4940093 DOI: 10.3892/mmr.2016.5428] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 04/25/2016] [Indexed: 12/25/2022] Open
Abstract
Congenital heart disease (CHD) is a complex illness with high rates of morbidity and mortality. In embryonic development, the heart is the first formed organ, which is strictly controlled by gene regulatory networks, including transcription factors, signaling pathways, epigenetic factors and microRNAs. Bone morphogenetic protein (BMP)-2 and -4 are essential in cardiogenesis as they can induce the expression of transcription factors, NKX2-5 and GATA binding protein 4, which are important in the development of the heart. The inhibition of BMP-2 and 4- inhibits the late expression of NKX2-5 and affects cardiac differentiation. The aim of the present study was to investigate whether BMP-2 and -4 variations may be associated with CHD in Chinese Han populations. The rs1049007, rs235768 and rs17563 single nucleotide polymorphisms (SNPs), which are genetic variations located within the translated region of the BMP-2 and -4, were evaluated in 230 patients with CHD from the Chinese Han population and 160 non CHD control individuals. Statistical analyses were performed using the χ2 test, implemented using SPSS software (version 13.0). The Hardy Weinberg equilibrium test was performed on the population using online Online Encyclopedia for Genetic Epidemiology studies software, and multiple-sequence alignments of the BMP proteins were performed using Vector NTI software. No statistically significant associations were identified between these genetic variations and the risk of CHD (rs1049007, P value=0.560; rs235768, P value=0.972; rs17563, P value=0.787). In addition, no correlation was found between the patients with CHD and the non-CHD control individuals. Therefore, the rs1049007, rs235768 and rs17563 genetic variations of BMP-2 were not associated with CHD in the Chinese Han population.
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Affiliation(s)
- Fei-Feng Li
- Genomics Research Center (one of the State‑Key Laboratory of Biopharmaceutical Engineering), Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Xia Deng
- Genomics Research Center (one of the State‑Key Laboratory of Biopharmaceutical Engineering), Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Jing Zhou
- Intensive Care Unit, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Peng Yan
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Er-Ying Zhao
- Genomics Research Center (one of the State‑Key Laboratory of Biopharmaceutical Engineering), Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Shu-Lin Liu
- Genomics Research Center (one of the State‑Key Laboratory of Biopharmaceutical Engineering), Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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