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1
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Clark LK, Cullati SN. Activation is only the beginning: mechanisms that tune kinase substrate specificity. Biochem Soc Trans 2025:BST20241420. [PMID: 39907081 DOI: 10.1042/bst20241420] [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: 10/22/2024] [Accepted: 10/29/2024] [Indexed: 02/06/2025]
Abstract
Kinases are master coordinators of cellular processes, but to appropriately respond to the changing cellular environment, each kinase must recognize its substrates, target only those proteins on the correct amino acids, and in many cases, only phosphorylate a subset of potential substrates at any given time. Therefore, regulation of kinase substrate specificity is paramount to proper cellular function, and multiple mechanisms can be employed to achieve specificity. At the smallest scale, characteristics of the substrate such as its linear peptide motif and three-dimensional structure must be complementary to the substrate binding surface of the kinase. This surface is dynamically shaped by the activation loop and surrounding region of the substrate binding groove, which can adopt multiple conformations, often influenced by post-translational modifications. Domain-scale conformational changes can also occur, such as the interaction with pseudosubstrate domains or other regulatory domains in the kinase. Kinases may multimerize or form complexes with other proteins that influence their structure, function, and/or subcellular localization at different times and in response to different signals. This review will illustrate these mechanisms by examining recent work on four serine/threonine kinases: Aurora B, CaMKII, GSK3β, and CK1δ. We find that these mechanisms are often shared by this diverse set of kinases in diverse cellular contexts, so they may represent common strategies that cells use to regulate cell signaling, and it will be enlightening to continue to learn about the depth and robustness of kinase substrate specificity in additional systems.
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Affiliation(s)
- Landon K Clark
- Department of Chemistry, Western Washington University, Bellingham, WA, U.S.A
| | - Sierra N Cullati
- Department of Chemistry, Western Washington University, Bellingham, WA, U.S.A
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2
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Rodgers SJ, Mitchell CA, Ooms LM. The mechanisms of class 1A PI3K and Wnt/β-catenin coupled signaling in breast cancer. Biochem Soc Trans 2023; 51:1459-1472. [PMID: 37471270 PMCID: PMC10586779 DOI: 10.1042/bst20220866] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/08/2023] [Accepted: 07/05/2023] [Indexed: 07/22/2023]
Abstract
The class IA PI3K signaling pathway is activated by growth factor stimulation and regulates a signaling cascade that promotes diverse events including cell growth, proliferation, migration and metabolism. PI3K signaling is one of the most commonly hyperactivated pathways in breast cancer, leading to increased tumor growth and progression. PI3K hyperactivation occurs via a number of genetic and epigenetic mechanisms including mutation or amplification of PIK3CA, the gene encoding the p110α subunit of PI3Kα, as well as via dysregulation of the upstream growth factor receptors or downstream signaling effectors. Over the past decade, extensive efforts to develop therapeutics that suppress oncogenic PI3K signaling have been undertaken. Although FDA-approved PI3K inhibitors are now emerging, their clinical success remains limited due to adverse effects and negative feedback mechanisms which contribute to their reduced efficacy. There is an emerging body of evidence demonstrating crosstalk between the PI3K and Wnt/β-catenin pathways in breast cancer. However, PI3K exhibits opposing effects on Wnt/β-catenin signaling in distinct tumor subsets, whereby PI3K promotes Wnt/β-catenin activation in ER+ cancers, but paradoxically suppresses this pathway in ER- breast cancers. This review discusses the molecular mechanisms for PI3K-Wnt crosstalk in breast cancer, and how Wnt-targeted therapies have the potential to contribute to treatment regimens for breast cancers with PI3K dysregulation.
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Affiliation(s)
- Samuel J. Rodgers
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Christina A. Mitchell
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Lisa M. Ooms
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
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3
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Gavagan M, Jameson N, Zalatan JG. The Axin scaffold protects the kinase GSK3β from cross-pathway inhibition. eLife 2023; 12:e85444. [PMID: 37548359 PMCID: PMC10442075 DOI: 10.7554/elife.85444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 08/04/2023] [Indexed: 08/08/2023] Open
Abstract
Multiple signaling pathways regulate the kinase GSK3β by inhibitory phosphorylation at Ser9, which then occupies the GSK3β priming pocket and blocks substrate binding. Since this mechanism should affect GSK3β activity toward all primed substrates, it is unclear why Ser9 phosphorylation does not affect other GSK3β-dependent pathways, such as Wnt signaling. We used biochemical reconstitution and cell culture assays to evaluate how Wnt-associated GSK3β is insulated from cross-activation by other signals. We found that the Wnt-specific scaffold protein Axin allosterically protects GSK3β from phosphorylation at Ser9 by upstream kinases, which prevents accumulation of pS9-GSK3β in the Axin•GSK3β complex. Scaffold proteins that protect bound proteins from alternative pathway reactions could provide a general mechanism to insulate signaling pathways from improper crosstalk.
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Affiliation(s)
- Maire Gavagan
- Department of Chemistry, University of WashingtonSeattleUnited States
| | - Noel Jameson
- Department of Chemistry, University of WashingtonSeattleUnited States
| | - Jesse G Zalatan
- Department of Chemistry, University of WashingtonSeattleUnited States
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4
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Davies EM, Gurung R, Le KQ, Roan KT, Harvey RP, Mitchell GM, Schwarz Q, Mitchell CA. PI(4,5)P 2-dependent regulation of endothelial tip cell specification contributes to angiogenesis. SCIENCE ADVANCES 2023; 9:eadd6911. [PMID: 37000875 PMCID: PMC10065449 DOI: 10.1126/sciadv.add6911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 02/24/2023] [Indexed: 06/19/2023]
Abstract
Dynamic positioning of endothelial tip and stalk cells, via the interplay between VEGFR2 and NOTCH signaling, is essential for angiogenesis. VEGFR2 activates PI3K, which phosphorylates PI(4,5)P2 to PI(3,4,5)P3, activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P2 hydrolysis by the phosphoinositide-5-phosphatase, INPP5K, contributes to angiogenesis. INPP5K ablation disrupted tip cell specification and impaired embryonic angiogenesis associated with enhanced DLL4/NOTCH signaling. INPP5K degraded a pool of PI(4,5)P2 generated by PIP5K1C phosphorylation of PI(4)P in endothelial cells. INPP5K ablation increased PI(4,5)P2, thereby releasing β-catenin from the plasma membrane, and concurrently increased PI(3,4,5)P3-dependent AKT activation, conditions that licensed DLL4/NOTCH transcription. Suppression of PI(4,5)P2 in INPP5K-siRNA cells by PIP5K1C-siRNA, restored β-catenin membrane localization and normalized AKT signaling. Pharmacological NOTCH or AKT inhibition in vivo or genetic β-catenin attenuation rescued angiogenesis defects in INPP5K-null mice. Therefore, PI(4,5)P2 is critical for β-catenin/DLL4/NOTCH signaling, which governs tip cell specification during angiogenesis.
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Affiliation(s)
- Elizabeth M. Davies
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
| | - Rajendra Gurung
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
| | - Kai Qin Le
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
| | - Katherine T. T. Roan
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
| | - Richard P. Harvey
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia
- School of Clinical Medicine and School of Biotechnology and Biomolecular Science, University of New South Wales, Kensington, New South Wales 2052, Australia
| | - Geraldine M. Mitchell
- O’Brien Institute Department of St Vincent’s Institute and University of Melbourne, Department of Surgery, St. Vincent’s Hospital, Fitzroy, Victoria 3065, Australia
- Health Sciences Faculty, Australian Catholic University, Fitzroy, Victoria 3065, Australia
| | - Quenten Schwarz
- Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia 5001, Australia
| | - Christina A. Mitchell
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
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5
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Feedback in the β-catenin destruction complex imparts bistability and cellular memory. Proc Natl Acad Sci U S A 2023; 120:e2208787120. [PMID: 36598937 PMCID: PMC9926258 DOI: 10.1073/pnas.2208787120] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Wnt ligands are considered classical morphogens, for which the strength of the cellular response is proportional to the concentration of the ligand. Herein, we show an emergent property of bistability arising from feedback among the Wnt destruction complex proteins that target the key transcriptional co-activator β-catenin for degradation. Using biochemical reconstitution, we identified positive feedback between the scaffold protein Axin and the kinase glycogen synthase kinase 3 (GSK3). Theoretical modeling of this feedback between Axin and GSK3 suggested that the activity of the destruction complex exhibits bistable behavior. We experimentally confirmed these predictions by demonstrating that cellular cytoplasmic β-catenin concentrations exhibit an "all-or-none" response with sustained memory (hysteresis) of the signaling input. This bistable behavior was transformed into a graded response and memory was lost through inhibition of GSK3. These findings provide a mechanism for establishing decisive, switch-like cellular response and memory upon Wnt pathway stimulation.
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6
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Fleming-de-Moraes CD, Rocha MR, Tessmann JW, de Araujo WM, Morgado-Diaz JA. Crosstalk between PI3K/Akt and Wnt/β-catenin pathways promote colorectal cancer progression regardless of mutational status. Cancer Biol Ther 2022; 23:1-13. [PMID: 35944058 PMCID: PMC9367664 DOI: 10.1080/15384047.2022.2108690] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The PI3K/Akt and Wnt/β-catenin pathways play an important role in the acquisition of the malignant phenotype in cancer. However, there are few data regarding the role of the interplay between both pathways in colorectal cancer (CRC) progression. The mutational status and the clinicopathological characteristics of PI3K/Akt and Wnt/β-catenin pathways were accessed by bioinformatic analysis whereas that the impact of the interplay between the activity of both pathways to explain tumorigenic potential was performed in vitro using IGF-1 and Wnt3a treatments in CRC cell models. The mutational status of these pathways did not influence the survival of CRC patients, but an association between clinicopathological characteristics in patients with mutations in one, but not in both pathways was observed. A potentiating effect on the activation of both pathways and enhanced cellular migration and proliferation was observed when both pathways were activated simultaneously with IGF-1 and Wnt3a. In addition, these effects were hindered after pretreatment with LY294002, a specific PI3K inhibitor, suggesting some dependence between these two signaling cascades. Our findings show that, regardless of mutational status, there is an interplay between the activity of PI3K/Akt and Wnt/β-catenin pathways that contributes to events related to CRC progression and that the reversal of such events using a PI3K inhibitor highlights the value of targeting these pathways for potential directed therapies in CRC patients.
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Affiliation(s)
- Cassio Dejair Fleming-de-Moraes
- Cellular and Molecular Oncobiology Program, Cellular Dynamic and Structure Group, Instituto Nacional de Cancer - INCA, Rio de Janeiro, Brazil
| | - Murilo Ramos Rocha
- Cellular and Molecular Oncobiology Program, Cellular Dynamic and Structure Group, Instituto Nacional de Cancer - INCA, Rio de Janeiro, Brazil
| | - Josiane Weber Tessmann
- Cellular and Molecular Oncobiology Program, Cellular Dynamic and Structure Group, Instituto Nacional de Cancer - INCA, Rio de Janeiro, Brazil
| | - Wallace Martins de Araujo
- Cellular and Molecular Oncobiology Program, Cellular Dynamic and Structure Group, Instituto Nacional de Cancer - INCA, Rio de Janeiro, Brazil.,Institute of Biological and Health Sciences, Federal Rural University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jose Andres Morgado-Diaz
- Cellular and Molecular Oncobiology Program, Cellular Dynamic and Structure Group, Instituto Nacional de Cancer - INCA, Rio de Janeiro, Brazil
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7
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Gui T, Burgering BMT. FOXOs: masters of the equilibrium. FEBS J 2022; 289:7918-7939. [PMID: 34610198 PMCID: PMC10078705 DOI: 10.1111/febs.16221] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/22/2021] [Accepted: 10/04/2021] [Indexed: 01/14/2023]
Abstract
Forkhead box O (FOXO) transcription factors (TFs) are a subclass of the larger family of forkhead TFs. Mammalians express four members FOXO1, FOXO3, FOXO4, and FOXO6. The interest in FOXO function stems mostly from their observed role in determining lifespan, where in model organisms, increased FOXO activity results in extended lifespan. FOXOs act as downstream of several signaling pathway and are extensively regulated through post-translational modifications. The transcriptional program activated by FOXOs in various cell types, organisms, and under various conditions has been described and has shed some light on what the critical transcriptional targets are in mediating FOXO function. At the cellular level, these studies have revealed a role for FOXOs in cell metabolism, cellular redox, cell proliferation, DNA repair, autophagy, and many more. The general picture that emerges hereof is that FOXOs act to preserve equilibrium, and they are important for cellular homeostasis. Here, we will first briefly summarize the general knowledge of FOXO regulation and possible functions. We will use genomic stability to illustrate how FOXOs ensure homeostasis. Genomic stability is critical for maintaining genetic integrity, and therefore preventing disease. However, genomic mutations need to occur during lifetime to enable evolution, yet their accumulation is believed to be causative to aging. Therefore, the role of FOXO in genomic stability may underlie its role in lifespan and aging. Finally, we will come up with questions on some of the unknowns in FOXO function, the answer(s) to which we believe will further our understanding of FOXO function and ultimately may help to understand lifespan and its consequences.
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Affiliation(s)
- Tianshu Gui
- Molecular Cancer Research, Center Molecular Medicine, University Medical Center Utrecht and the Oncode Institute, The Netherlands
| | - Boudewijn M T Burgering
- Molecular Cancer Research, Center Molecular Medicine, University Medical Center Utrecht and the Oncode Institute, The Netherlands
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8
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Chandrasekera P, Perfetto M, Lu C, Zhuo M, Bahudhanapati H, Li J, Chen WC, Kulkarni P, Christian L, Liu J, Yien YY, Yu C, Wei S. Metalloprotease ADAM9 cleaves ephrin-B ligands and differentially regulates Wnt and mTOR signaling downstream of Akt kinase in colorectal cancer cells. J Biol Chem 2022; 298:102225. [PMID: 35780836 PMCID: PMC9358476 DOI: 10.1016/j.jbc.2022.102225] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 12/02/2022] Open
Abstract
Ephrin-B signaling has been implicated in many normal and pathological processes, including neural crest development and tumor metastasis. We showed previously that proteolysis of ephrin-B ligands by the disintegrin metalloprotease ADAM13 is necessary for canonical Wnt signal activation and neural crest induction in Xenopus, but it was unclear if these mechanisms are conserved in mammals. Here, we report that mammalian ADAM9 cleaves ephrin-B1 and ephrin-B2 and can substitute for Xenopus ADAM13 to induce the neural crest. We found that ADAM9 expression is elevated in human colorectal cancer (CRC) tissues and that knockdown (KD) of ADAM9 inhibits the migration and invasion of SW620 and HCT116 CRC cells by reducing the activity of Akt kinase, which is antagonized by ephrin-Bs. Akt is a signaling node that activates multiple downstream pathways, including the Wnt and mTOR pathways, both of which can promote CRC cell migration/invasion. Surprisingly, we also found that KD of ADAM9 downregulates Wnt signaling but has negligible effects on mTOR signaling in SW620 cells; in contrast, mTOR activity is suppressed while Wnt signaling remains unaffected by ADAM9 KD in HCT116 cells. These results suggest that mammalian ADAM9 cleaves ephrin-Bs to derepress Akt and promote CRC migration and invasion; however, the signaling pathways downstream of Akt are differentially regulated by ADAM9 in different CRC cell lines, reflecting the heterogeneity of CRC cells in responding to manipulations of upstream Akt regulators.
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Affiliation(s)
| | - Mark Perfetto
- Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Biology, West Virginia University, Morgantown, West Virginia, USA; Pittsburgh Heart, Lung and Blood Vascular Medicine Institute and Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Congyu Lu
- Department of Biological Sciences, University of Delaware, Newark, Delaware, USA
| | - Minghui Zhuo
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | | | - Jiejing Li
- Department of Biology, West Virginia University, Morgantown, West Virginia, USA; Department of Clinical Laboratory, The Affiliated Hospital of KMUST, Medical School, Kunming University of Science and Technology, Kunming, China
| | - Wei-Chih Chen
- Department of Biology, West Virginia University, Morgantown, West Virginia, USA
| | - Pallavi Kulkarni
- Department of Biological Sciences, University of Delaware, Newark, Delaware, USA
| | - Laura Christian
- Department of Biology, West Virginia University, Morgantown, West Virginia, USA
| | - Jun Liu
- Department of Biochemistry and Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Yvette Y Yien
- Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Pittsburgh Heart, Lung and Blood Vascular Medicine Institute and Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Chundong Yu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Shuo Wei
- Department of Biological Sciences, University of Delaware, Newark, Delaware, USA.
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9
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Liu Z, Chen T, Zhang S, Yang T, Gong Y, Deng HW, Bai D, Tian W, Chen Y. Discovery and functional assessment of a novel adipocyte population driven by intracellular Wnt/β-catenin signaling in mammals. eLife 2022; 11:77740. [PMID: 35503096 PMCID: PMC9064292 DOI: 10.7554/elife.77740] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/26/2022] [Indexed: 02/05/2023] Open
Abstract
Wnt/β-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/β-catenin signaling, as revealed by the Tcf/Lef-GFP reporter allele, in embryonic and adult mouse fat depots, named as Wnt+ adipocytes. We showed that this β-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survival. Such adipocytes are distinct from classical ones in transcriptomic and genomic signatures and can be induced from various sources of mesenchymal stromal cells including human cells. Genetic lineage-tracing and targeted cell ablation studies revealed that these adipocytes convert into beige adipocytes directly and are also required for beige fat recruitment under thermal challenge, demonstrating both cell autonomous and non-cell autonomous roles in adaptive thermogenesis. Furthermore, mice bearing targeted ablation of these adipocytes exhibited glucose intolerance, while mice receiving exogenously supplied such cells manifested enhanced glucose utilization. Our studies uncover a unique adipocyte population in regulating beiging in adipose tissues and systemic glucose homeostasis.
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Affiliation(s)
- Zhi Liu
- Department of Cell and Molecular Biology, Tulane University, New Orleans, United States.,State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Tian Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, United States.,State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Sicheng Zhang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, United States.,State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Tianfang Yang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, United States
| | - Yun Gong
- Tulane Center of Biomedical Informatics and Genomic, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, United States
| | - Hong-Wen Deng
- Tulane Center of Biomedical Informatics and Genomic, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, United States
| | - Ding Bai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Weidong Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - YiPing Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, United States
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10
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Upadhyay J, Ansari MN, Samad A, Sayana A. Dysregulation of multiple signaling pathways: A possible cause of cerebral palsy. Exp Biol Med (Maywood) 2022; 247:779-787. [PMID: 35253451 DOI: 10.1177/15353702221081022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Cerebral palsy (CP) is a lifelong disability characterized by the impairment of brain functions that result in improper posture and abnormal motor patterns. Understanding this brain abnormality and the role of genetic, epigenetic, and non-genetic factors such as signaling pathway dysregulation and cytokine dysregulation in the pathogenesis of CP is a complex process. Hypoxic-ischemic injury and prematurity are two well-known contributors of CP. Like in the case of other neurodevelopmental disorders such as intellectual disability and autism, the genomic constituents in CP are highly complex. The neuroinflammation that is triggered by maternal cytokine response plays a critical role in the pathogenesis of fetal inflammation response, which is one of the contributing factors of CP, and it continues even after the birth of children suffering from CP. Canonical Wnt signaling pathway is important for the development of mammalian fetal brain and it regulates distinct processes including neurogenesis. The glycogen synthase kinase-3 (GSK-3) antagonistic activity in the Wnt signaling pathway plays a crucial role in neurogenesis and neural development. In this review, we investigated several genetic and non-genetic pathways that are involved in the pathogenesis of CP and their regulation, impairment, and implications for causing CP during embryonic growth and developmental period. Investigating the role of these pathways help to develop novel therapeutic interventions and biomarkers for early diagnosis and treatment. This review also helps us to comprehend the mechanical approach of various signaling pathways, as well as their consequences and relevance in the understanding of CP.
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Affiliation(s)
- Jyoti Upadhyay
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Mohd Nazam Ansari
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Abdul Samad
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tishk International University, Erbil 44001, Iraq
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11
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Abstract
The Wnt pathway is central to a host of developmental and disease-related processes. The remarkable conservation of this intercellular signaling cascade throughout metazoan lineages indicates that it coevolved with multicellularity to regulate the generation and spatial arrangement of distinct cell types. By regulating cell fate specification, mitotic activity, and cell polarity, Wnt signaling orchestrates development and tissue homeostasis, and its dysregulation is implicated in developmental defects, cancer, and degenerative disorders. We review advances in our understanding of this key pathway, from Wnt protein production and secretion to relay of the signal in the cytoplasm of the receiving cell. We discuss the evolutionary history of this pathway as well as endogenous and synthetic modulators of its activity. Finally, we highlight remaining gaps in our knowledge of Wnt signal transduction and avenues for future research. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Ellen Youngsoo Rim
- Howard Hughes Medical Institute, Department of Developmental Biology, and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA;
| | - Hans Clevers
- Hubrecht Institute and Oncode Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands
| | - Roel Nusse
- Howard Hughes Medical Institute, Department of Developmental Biology, and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA;
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12
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Bourgeois B, Gui T, Hoogeboom D, Hocking HG, Richter G, Spreitzer E, Viertler M, Richter K, Madl T, Burgering BMT. Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function. Cell Rep 2021; 36:109446. [PMID: 34320339 DOI: 10.1016/j.celrep.2021.109446] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 04/15/2021] [Accepted: 07/02/2021] [Indexed: 12/11/2022] Open
Abstract
Transcription factors harbor defined regulatory intrinsically disordered regions (IDRs), which raises the question of how they mediate binding to structured co-regulators and modulate their activity. Here, we present a detailed molecular regulatory mechanism of Forkhead box O4 (FOXO4) by the structured transcriptional co-regulator β-catenin. We find that the disordered FOXO4 C-terminal region, which contains its transactivation domain, binds β-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation. Binding of β-catenin competes with the autoinhibitory interaction of the FOXO4 disordered region with its DNA-binding Forkhead domain, and thereby enhances FOXO4 transcriptional activity. Furthermore, we show that binding of the β-catenin inhibitor protein ICAT is compatible with FOXO4 binding to β-catenin, suggesting that ICAT acts as a molecular switch between anti-proliferative FOXO and pro-proliferative Wnt/TCF/LEF signaling. These data illustrate how the interplay of IDRs, post-translational modifications, and co-factor binding contribute to transcription factor function.
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Affiliation(s)
- Benjamin Bourgeois
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Tianshu Gui
- Oncode Institute and Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Diana Hoogeboom
- Oncode Institute and Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Henry G Hocking
- Department Chemie, Technische Universität München, 85747 Garching, Germany
| | - Gesa Richter
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Emil Spreitzer
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Martin Viertler
- Department Chemie, Technische Universität München, 85747 Garching, Germany
| | - Klaus Richter
- Department Chemie, Technische Universität München, 85747 Garching, Germany
| | - Tobias Madl
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
| | - Boudewijn M T Burgering
- Oncode Institute and Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
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13
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INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer. Nat Commun 2021; 12:3140. [PMID: 34035258 PMCID: PMC8149851 DOI: 10.1038/s41467-021-23241-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 04/16/2021] [Indexed: 01/17/2023] Open
Abstract
INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.
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14
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Kafka A, Bukovac A, Brglez E, Jarmek AM, Poljak K, Brlek P, Žarković K, Njirić N, Pećina-Šlaus N. Methylation Patterns of DKK1, DKK3 and GSK3β Are Accompanied with Different Expression Levels in Human Astrocytoma. Cancers (Basel) 2021; 13:cancers13112530. [PMID: 34064046 PMCID: PMC8196684 DOI: 10.3390/cancers13112530] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 01/24/2023] Open
Abstract
In the present study, we investigated genetic and epigenetic changes and protein expression levels of negative regulators of Wnt signaling, DKK1, DKK3, and APC as well as glycogen synthase kinase 3 (GSK3β) and β-catenin in 64 human astrocytomas of grades II-IV. Methylation-specific PCR revealed promoter methylation of DKK1, DKK3, and GSK3β in 38%, 43%, and 18% of samples, respectively. Grade IV comprised the lowest number of methylated GSK3β cases and highest of DKK3. Evaluation of the immunostaining using H-score was performed for β-catenin, both total and unphosphorylated (active) forms. Additionally, active (pY216) and inactive (pS9) forms of GSK3β protein were also analyzed. Spearman's correlation confirmed the prevalence of β-catenin's active form (rs = 0.634, p < 0.001) in astrocytoma tumor cells. The Wilcoxon test revealed that astrocytoma with higher levels of the active pGSK3β-Y216 form had lower expression levels of its inactive form (p < 0.0001, Z = -5.332). Changes in APC's exon 11 were observed in 44.44% of samples by PCR/RFLP. Astrocytomas with changes of APC had higher H-score values of total β-catenin compared to the group without genetic changes (t = -2.264, p = 0.038). Furthermore, a positive correlation between samples with methylated DKK3 promoter and the expression of active pGSK3β-Y216 (rs = 0.356, p = 0.011) was established. Our results emphasize the importance of methylation for the regulation of Wnt signaling. Large deletions of the APC gene associated with increased β-catenin levels, together with oncogenic effects of both β-catenin and GSK3β, are clearly involved in astrocytoma evolution. Our findings contribute to a better understanding of the etiology of gliomas. Further studies should elucidate the clinical and therapeutic relevance of the observed molecular alterations.
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Affiliation(s)
- Anja Kafka
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10 000 Zagreb, Croatia; (A.B.); (E.B.); (A.-M.J.); (K.P.); (P.B.); (N.N.); (N.P.-Š.)
- Department of Biology, School of Medicine, University of Zagreb, Šalata 3, 10 000 Zagreb, Croatia
- Correspondence:
| | - Anja Bukovac
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10 000 Zagreb, Croatia; (A.B.); (E.B.); (A.-M.J.); (K.P.); (P.B.); (N.N.); (N.P.-Š.)
- Department of Biology, School of Medicine, University of Zagreb, Šalata 3, 10 000 Zagreb, Croatia
| | - Emilija Brglez
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10 000 Zagreb, Croatia; (A.B.); (E.B.); (A.-M.J.); (K.P.); (P.B.); (N.N.); (N.P.-Š.)
| | - Ana-Marija Jarmek
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10 000 Zagreb, Croatia; (A.B.); (E.B.); (A.-M.J.); (K.P.); (P.B.); (N.N.); (N.P.-Š.)
| | - Karolina Poljak
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10 000 Zagreb, Croatia; (A.B.); (E.B.); (A.-M.J.); (K.P.); (P.B.); (N.N.); (N.P.-Š.)
| | - Petar Brlek
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10 000 Zagreb, Croatia; (A.B.); (E.B.); (A.-M.J.); (K.P.); (P.B.); (N.N.); (N.P.-Š.)
| | - Kamelija Žarković
- Department of Pathology, School of Medicine, University of Zagreb, Šalata 10, 10 000 Zagreb, Croatia;
- Division of Pathology, University Hospital Center “Zagreb”, Kišpatićeva 12, 10 000 Zagreb, Croatia
| | - Niko Njirić
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10 000 Zagreb, Croatia; (A.B.); (E.B.); (A.-M.J.); (K.P.); (P.B.); (N.N.); (N.P.-Š.)
- Department of Neurosurgery, University Hospital Center “Zagreb”, School of Medicine, University of Zagreb, Kišpatićeva 12, 10 000 Zagreb, Croatia
| | - Nives Pećina-Šlaus
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10 000 Zagreb, Croatia; (A.B.); (E.B.); (A.-M.J.); (K.P.); (P.B.); (N.N.); (N.P.-Š.)
- Department of Biology, School of Medicine, University of Zagreb, Šalata 3, 10 000 Zagreb, Croatia
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15
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Glibo M, Serman A, Karin-Kujundzic V, Bekavac Vlatkovic I, Miskovic B, Vranic S, Serman L. The role of glycogen synthase kinase 3 (GSK3) in cancer with emphasis on ovarian cancer development and progression: A comprehensive review. Bosn J Basic Med Sci 2021; 21:5-18. [PMID: 32767962 PMCID: PMC7861620 DOI: 10.17305/bjbms.2020.5036] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 08/04/2020] [Indexed: 12/27/2022] Open
Abstract
Glycogen synthase kinase 3 (GSK3) is a monomeric serine-threonine kinase discovered in 1980 in a rat skeletal muscle. It has been involved in various cellular processes including embryogenesis, immune response, inflammation, apoptosis, autophagy, wound healing, neurodegeneration, and carcinogenesis. GSK3 exists in two different isoforms, GSK3α and GSK3β, both containing seven antiparallel beta-plates, a short linking part and an alpha helix, but coded by different genes and variously expressed in human tissues. In the current review, we comprehensively appraise the current literature on the role of GSK3 in various cancers with emphasis on ovarian carcinoma. Our findings indicate that the role of GSK3 in ovarian cancer development cannot be decisively determined as the currently available data support both prooncogenic and tumor-suppressive effects. Likewise, the clinical impact of GSK3 expression on ovarian cancer patients and its potential therapeutic implications are also limited. Further studies are needed to fully elucidate the pathophysiological and clinical implications of GSK3 activity in ovarian cancer.
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Affiliation(s)
- Mislav Glibo
- Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alan Serman
- Centre of Excellence in Reproductive and Regenerative Medicine, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Obstetrics and Gynecology, School of Medicine, University of Zagreb, Zagreb, Croatia; Clinic of Obstetrics and Gynecology, Clinical Hospital "Sveti Duh", Zagreb, Croatia
| | - Valentina Karin-Kujundzic
- Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia; Centre of Excellence in Reproductive and Regenerative Medicine, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Ivanka Bekavac Vlatkovic
- Centre of Excellence in Reproductive and Regenerative Medicine, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Obstetrics and Gynecology, School of Medicine, University of Zagreb, Zagreb, Croatia; Clinic of Obstetrics and Gynecology, Clinical Hospital "Sveti Duh", Zagreb, Croatia
| | - Berivoj Miskovic
- Centre of Excellence in Reproductive and Regenerative Medicine, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Obstetrics and Gynecology, School of Medicine, University of Zagreb, Zagreb, Croatia; Clinic of Obstetrics and Gynecology, Clinical Hospital "Sveti Duh", Zagreb, Croatia
| | - Semir Vranic
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Ljiljana Serman
- Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia; Centre of Excellence in Reproductive and Regenerative Medicine, University of Zagreb School of Medicine, Zagreb, Croatia
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16
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Perfetto M, Xu X, Lu C, Shi Y, Yousaf N, Li J, Yien YY, Wei S. The RNA helicase DDX3 induces neural crest by promoting AKT activity. Development 2021; 148:dev.184341. [PMID: 33318149 DOI: 10.1242/dev.184341] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 12/02/2020] [Indexed: 01/02/2023]
Abstract
Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many individuals carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Xenopus tropicalis as a model, we show that DDX3 is required for normal NC induction and craniofacial morphogenesis by regulating AKT kinase activity. Depletion of DDX3 decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3β, leading to reduced levels of β-catenin and Snai1: two GSK3β substrates that are crucial for NC induction. DDX3 function in regulating these downstream signaling events during NC induction is likely mediated by RAC1, a small GTPase whose translation depends on the RNA helicase activity of DDX3. These results suggest an evolutionarily conserved role of DDX3 in NC development by promoting AKT activity, and provide a potential mechanism for the NC-related birth defects displayed by individuals harboring mutations in DDX3 and its downstream effectors in this signaling cascade.
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Affiliation(s)
- Mark Perfetto
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.,Department of Biology, West Virginia University, Morgantown, WV 26506, USA
| | - Xiaolu Xu
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Congyu Lu
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Yu Shi
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Natasha Yousaf
- Department of Biology, West Virginia University, Morgantown, WV 26506, USA
| | - Jiejing Li
- Department of Biology, West Virginia University, Morgantown, WV 26506, USA.,Department of Clinical Laboratory, The Affiliated Hospital of KMUST, Medical School, Kunming University of Science and Technology, Kunming 650032, China
| | - Yvette Y Yien
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Shuo Wei
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
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17
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Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int J Mol Sci 2020; 21:E4507. [PMID: 32630372 PMCID: PMC7350257 DOI: 10.3390/ijms21124507] [Citation(s) in RCA: 374] [Impact Index Per Article: 74.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/22/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022] Open
Abstract
Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.
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Affiliation(s)
| | | | | | - Helen B. Pearson
- The European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, Wales, UK; (B.Y.S.); (M.S.D.); (M.J.S.)
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18
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Gavagan M, Fagnan E, Speltz EB, Zalatan JG. The Scaffold Protein Axin Promotes Signaling Specificity within the Wnt Pathway by Suppressing Competing Kinase Reactions. Cell Syst 2020; 10:515-525.e5. [PMID: 32553184 DOI: 10.1016/j.cels.2020.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 04/02/2020] [Accepted: 05/15/2020] [Indexed: 10/24/2022]
Abstract
Scaffold proteins are thought to promote signaling specificity by accelerating reactions between bound kinase and substrate proteins. To test the long-standing hypothesis that the scaffold protein Axin accelerates glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation of β-catenin in the Wnt signaling network, we measured GSK3β reaction rates with multiple substrates in a minimal, biochemically reconstituted system. We observed an unexpectedly small, ∼2-fold Axin-mediated rate increase for the β-catenin reaction when measured in isolation. In contrast, when both β-catenin and non-Wnt pathway substrates are present, Axin accelerates the β-catenin reaction by preventing competition with alternative substrates. At high competitor concentrations, Axin produces >10-fold rate effects. Thus, while Axin alone does not markedly accelerate the β-catenin reaction, in physiological settings where multiple GSK3β substrates are present, Axin may promote signaling specificity by suppressing interactions with competing, non-Wnt pathway targets. This mechanism for scaffold-mediated control of competition enables a shared kinase to perform distinct functions in multiple signaling networks.
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Affiliation(s)
- Maire Gavagan
- Department of Chemistry, University of Washington, Seattle, WA 98195, USA
| | - Erin Fagnan
- Department of Chemistry, University of Washington, Seattle, WA 98195, USA
| | - Elizabeth B Speltz
- Department of Chemistry, University of Washington, Seattle, WA 98195, USA
| | - Jesse G Zalatan
- Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
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19
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Dong J, Xu X, Zhang Q, Yuan Z, Tan B. The PI3K/AKT pathway promotes fracture healing through its crosstalk with Wnt/β-catenin. Exp Cell Res 2020; 394:112137. [PMID: 32534061 DOI: 10.1016/j.yexcr.2020.112137] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/25/2020] [Accepted: 06/06/2020] [Indexed: 12/27/2022]
Abstract
PI3K/AKT is one of the key pathways that regulate cell behaviors including apoptosis, proliferation, and differentiation. Although previous studies have demonstrated that this pathway is a crucial regulator of osteoblasts, the role of PI3K/AKT in fracture healing remains unclear. It is well known that the Wnt/β-catenin pathway plays an essential role in bone regeneration. However, whether there exists crosstalk between Wnt/β-catenin and PI3K/AKT in regulating osteoblasts and bone repair has not been reported. To address these issues, we establish a stabilized fracture model in mice and show that PI3K inhibitor LY294002 substantially inhibits the bone healing process, suggesting that PI3K/AKT promotes fracture repair. More importantly, we report that PI3K/AKT increases phosphorylation of GSK-3β at Ser9 and phosphorylation of β-catenin at Ser552 in fracture callus and murine osteoblastic MC3T3-E1 cells, both of which lead to β-catenin stabilization, nuclear translocation, as well as β-catenin-mediated TCF-dependent transcription, suggesting that β-catenin is activated downstream of PI3K/AKT. Furthermore, we show that ICG001, the inhibitor of β-catenin transcriptional activity, attenuates PI3K/AKT-induced osteoblast proliferation, differentiation, and mineralization, indicating that the PI3K/AKT/β-catenin axis is functional in regulating osteoblasts. Notably, the PI3K/AKT pathway is also activated by Wnt3a and is involved in Wnt3a-induced osteoblast proliferation and differentiation. Hence, our results reveal the existence of a Wnt/PI3K/AKT/β-catenin signaling nexus in osteoblasts, highlighting complex crosstalk between PI3K/AKT and Wnt/β-catenin pathways that are critically implicated in fracture healing.
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Affiliation(s)
- Jun Dong
- Department of Orthopaedics, Shangdong Provincial Hospital, Shandong First Medical University, PR China
| | - Xiqiang Xu
- Department of Orthopaedics, Shangdong Provincial Hospital, Shandong First Medical University, PR China
| | - Qingyu Zhang
- Department of Orthopaedics, Shangdong Provincial Hospital, Shandong First Medical University, PR China
| | - Zenong Yuan
- Department of Orthopaedics, Shangdong Provincial Hospital, Shandong First Medical University, PR China
| | - Bingyi Tan
- Department of Orthopaedics, Shangdong Provincial Hospital, Shandong First Medical University, PR China.
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20
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Zhong Z, Virshup DM. Wnt Signaling and Drug Resistance in Cancer. Mol Pharmacol 2020; 97:72-89. [PMID: 31787618 DOI: 10.1124/mol.119.117978] [Citation(s) in RCA: 154] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/21/2019] [Indexed: 12/22/2022] Open
Abstract
Wnts are secreted proteins that bind to cell surface receptors to activate downstream signaling cascades. Normal Wnt signaling plays key roles in embryonic development and adult tissue homeostasis. The secretion of Wnt ligands, the turnover of Wnt receptors, and the signaling transduction are tightly regulated and fine-tuned to keep the signaling output "just right." Hyperactivated Wnt signaling due to recurrent genetic alterations drives several human cancers. Elevated Wnt signaling also confers resistance to multiple conventional and targeted cancer therapies through diverse mechanisms including maintaining the cancer stem cell population, enhancing DNA damage repair, facilitating transcriptional plasticity, and promoting immune evasion. Different classes of Wnt signaling inhibitors targeting key nodes of the pathway have been developed and show efficacy in treating Wnt-driven cancers and subverting Wnt-mediated therapy resistance in preclinical studies. Several of these inhibitors have advanced to clinical trials, both singly and in combination with other existing US Food and Drug Administration-approved anti-cancer modalities. In the near future, pharmacological inhibition of Wnt signaling may be a real choice for patients with cancer. SIGNIFICANCE STATEMENT: The latest insights in Wnt signaling, ranging from basic biology to therapeutic implications in cancer, are reviewed. Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.
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Affiliation(s)
- Zheng Zhong
- Department of Physiology, National University of Singapore, Singapore, Singapore (Z.Z.); Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore (Z.Z., D.M.V.); and Department of Pediatrics, Duke University, Durham, North Carolina (D.M.V.)
| | - David M Virshup
- Department of Physiology, National University of Singapore, Singapore, Singapore (Z.Z.); Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore (Z.Z., D.M.V.); and Department of Pediatrics, Duke University, Durham, North Carolina (D.M.V.)
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21
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Manoranjan B, Chokshi C, Venugopal C, Subapanditha M, Savage N, Tatari N, Provias JP, Murty NK, Moffat J, Doble BW, Singh SK. A CD133-AKT-Wnt signaling axis drives glioblastoma brain tumor-initiating cells. Oncogene 2019; 39:1590-1599. [PMID: 31695152 DOI: 10.1038/s41388-019-1086-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 10/23/2019] [Accepted: 10/25/2019] [Indexed: 12/18/2022]
Abstract
Mechanistic insight into signaling pathways downstream of surface receptors has been revolutionized with integrated cancer genomics. This has fostered current treatment modalities, namely immunotherapy, to capitalize on targeting key oncogenic signaling nodes downstream of a limited number of surface markers. Unfortunately, rudimentary mechanistic understanding of most other cell surface proteins has reduced the clinical utility of these markers. CD133 has reproducibly been shown to correlate with disease progression, recurrence, and poor overall survivorship in the malignant adult brain tumor, glioblastoma (GBM). Using several patient-derived CD133high and CD133low GBMs we describe intrinsic differences in determinants of stemness, which we owe to a CD133-AKT-Wnt signaling axis in which CD133 functions as a putative cell surface receptor for AKT-dependent Wnt activation. These findings may have implications for personalized oncology trials targeting PI3K/AKT or Wnt as both pathways may be activated independent of their canonical drivers, leading to treatment resistance and disease relapse.
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Affiliation(s)
- Branavan Manoranjan
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada.,McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.,Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada
| | - Chirayu Chokshi
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.,Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada
| | - Chitra Venugopal
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Minomi Subapanditha
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Neil Savage
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Nazanin Tatari
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.,Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada
| | - John P Provias
- Departments of Pathology, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada
| | - Naresh K Murty
- Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada
| | - Jason Moffat
- The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada
| | - Bradley W Doble
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.,Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada
| | - Sheila K Singh
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. .,Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada. .,Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
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22
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Xu Y, Zhang G, Zou C, Qi W, Gong Z, Zhang G, Ma G, Zhang W, Jiang P. Long non-coding RNA LINC01225 promotes proliferation, invasion and migration of gastric cancer via Wnt/β-catenin signalling pathway. J Cell Mol Med 2019; 23:7581-7591. [PMID: 31460694 PMCID: PMC6815774 DOI: 10.1111/jcmm.14627] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 06/10/2019] [Accepted: 08/05/2019] [Indexed: 12/24/2022] Open
Abstract
Emerging evidence has classified the aberrant expression of long non-coding RNAs (lncRNAs) as a basic signature of various malignancies including gastric cancer (GC). LINC01225 has been shown to act as a hepatocellular carcinoma-related gene, with its expression pattern and biological function not clarified in GC. Here, we verified that LINC01225 was up-regulated in tumour tissues and plasma of GC. Analysis with clinicopathological information suggested that up-regulation of LINC01225 was associated with advanced disease and poorer overall survival. Receiver operating characteristic (ROC) analysis showed that plasma LINC01225 had a moderate accuracy for diagnosis of GC. In addition, knockdown of LINC01225 led to retardation of cell proliferation, invasion and migration, and overexpression of LINC01225 showed the opposite effects. Mechanistic investigations showed that LINC01225 silencing inhibited epithelial-mesenchymal transition (EMT) process and attenuated Wnt/β-catenin signalling of GC. Furthermore, ectopic expression of Wnt1 or suppression of GSK-3β abolished the si-LINC01225-mediated suppression against EMT, thereby promoting cell proliferation, invasion and migration of GC. In conclusion, LINC01225 promotes the progression of GC through Wnt/β-catenin signalling pathway, and it may serve as a potential target or strategy for diagnosis or treatment of GC.
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Affiliation(s)
- Ying Xu
- Department of Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Guohua Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Zou
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Weidong Qi
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Zhigang Gong
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Guoliang Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Gui Ma
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Wenbo Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
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Becker J, Wilting J. WNT Signaling in Neuroblastoma. Cancers (Basel) 2019; 11:cancers11071013. [PMID: 31331081 PMCID: PMC6679057 DOI: 10.3390/cancers11071013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/17/2019] [Accepted: 07/18/2019] [Indexed: 01/09/2023] Open
Abstract
The term WNT (wingless-type MMTV integration site family) signaling comprises a complex molecular pathway consisting of ligands, receptors, coreceptors, signal transducers and transcriptional modulators with crucial functions during embryonic development, including all aspects of proliferation, morphogenesis and differentiation. Its involvement in cancer biology is well documented. Even though WNT signaling has been divided into mainly three distinct branches in the past, increasing evidence shows that some molecular hubs can act in various branches by exchanging interaction partners. Here we discuss developmental and clinical aspects of WNT signaling in neuroblastoma (NB), an embryonic tumor with an extremely broad clinical spectrum, ranging from spontaneous differentiation to fatal outcome. We discuss implications of WNT molecules in NB onset, progression, and relapse due to chemoresistance. In the light of the still too high number of NB deaths, new pathways must be considered.
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Affiliation(s)
- Juergen Becker
- Department of Anatomy and Cell Biology, University Medical School Goettingen, Kreuzbergring 36, 37075 Goettingen, Germany.
| | - Joerg Wilting
- Department of Anatomy and Cell Biology, University Medical School Goettingen, Kreuzbergring 36, 37075 Goettingen, Germany
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24
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Different expression of GSK3β and pS9GSK3β depending on phenotype of cervical cancer: possible association of GSK3β with squamous cell carcinoma and pS9GSK3β with adenocarcinoma. Obstet Gynecol Sci 2019; 62:157-165. [PMID: 31139591 PMCID: PMC6520545 DOI: 10.5468/ogs.2019.62.3.157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/04/2018] [Accepted: 12/12/2018] [Indexed: 12/19/2022] Open
Abstract
Objective This study aimed to analyze the expression pattern of glycogen synthase kinase 3β (GSK3β) and its phosphorylated forms, GSK3β phosphorylated at Ser9 (pS9GSK3β), and GSK3β phosphorylated at Tyr216 (pY216GSK3β), in cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC). Methods We performed immunohistochemical staining for GSK3β, pS9GSK3β, and pY216GSK3β in 64 SCC and 20 AC cases and compared their expression patterns between the 2 tumor types. Results Increased GSK3β and pS9GSK3β expression but decreased pY216GSK3β expression compared with that in the normal cervix were observed in both SCC and AC specimens. Specifically, the levels of GSK3β and pS9GSK3β were significantly increased in SCC and AC, respectively. GSK3β was localized in the nucleus and/or cytoplasm of SCC and AC cells. However, pS9GSK3β was predominantly localized in the membrane of AC cells, whereas it was present in the nucleus and/or cytoplasm of SCC cells. Conclusion The results suggest that the phosphorylation status of GSK3β changes during cervical cancer development and the different expression levels and patterns of GSK3β and pS9GSK3β are associated with the specific histologic phenotype of cervical cancer.
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25
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Islam R, Kim JG, Park Y, Cho JY, Cap KC, Kho AR, Chung WS, Suh SW, Park JB. Insulin induces phosphorylation of pyruvate dehydrogenase through RhoA activation pathway in HepG2 cells. FASEB J 2018; 33:2072-2083. [DOI: 10.1096/fj.201800917r] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Rokibul Islam
- Department of BiochemistryHallym UniversityChuncheonSouth Korea
- Institute of Cell Differentiation and AgingHallym UniversityChuncheonSouth Korea
- Department of Biotechnology and Genetic EngineeringFaculty of Applied Science and TechnologyIslamic UniversityKushtiaBangladesh
| | - Jae-Gyu Kim
- Department of BiochemistryHallym UniversityChuncheonSouth Korea
- Institute of Cell Differentiation and AgingHallym UniversityChuncheonSouth Korea
| | - Yohan Park
- Department of BiochemistryHallym UniversityChuncheonSouth Korea
| | - Jung-Yoon Cho
- Department of BiochemistryHallym UniversityChuncheonSouth Korea
- Institute of Cell Differentiation and AgingHallym UniversityChuncheonSouth Korea
| | - Kim-Cuong Cap
- Department of BiochemistryHallym UniversityChuncheonSouth Korea
| | - A-Ra Kho
- Department of PhysiologyHallym University College of MedicineHallym UniversityChuncheonSouth Korea
| | - Won-Suk Chung
- Department of Biological ScienceKorea Advanced Institute of Science and TechnologyDaejeonSouth Korea
| | - Sang-Won Suh
- Department of PhysiologyHallym University College of MedicineHallym UniversityChuncheonSouth Korea
- Hallym Clinical and Translational Research InstituteHallym UniversityChuncheonSouth Korea
| | - Jae-Bong Park
- Department of BiochemistryHallym UniversityChuncheonSouth Korea
- Institute of Cell Differentiation and AgingHallym UniversityChuncheonSouth Korea
- Hallym Clinical and Translational Research InstituteHallym UniversityChuncheonSouth Korea
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Safian D, Bogerd J, Schulz RW. Igf3 activates β-catenin signaling to stimulate spermatogonial differentiation in zebrafish. J Endocrinol 2018; 238:245-257. [PMID: 29941503 DOI: 10.1530/joe-18-0124] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023]
Abstract
Follicle-stimulating hormone (Fsh) is a major regulator of spermatogenesis, targeting somatic cell functions in the testes. We reported previously that zebrafish Fsh promoted the differentiation of type A undifferentiated spermatogonia (Aund) by stimulating the production of factors that advance germ cell differentiation, such as androgens, insulin-like peptide 3 (Insl3) and insulin-like growth factor 3 (Igf3). In addition, Fsh also modulated the transcript levels of several other genes, including some belonging to the Wnt signaling pathway. Here, we evaluated if and how Fsh utilizes part of the canonical Wnt pathway to regulate the development of spermatogonia. We quantified the proliferation activity and relative section areas occupied by Aund and type A differentiating (Adiff) spermatogonia and we analyzed the expression of selected genes in response to recombinant proteins and pharmacological inhibitors. We found that from the three downstream mediators of Fsh activity we examined, Igf3, but not 11-ketotestosterone or Insl3, modulated the transcript levels of two β-catenin sensitive genes (cyclinD1 and axin2). Using a zebrafish β-catenin signaling reporter line, we showed that Igf3 activated β-catenin signaling in type A spermatogonia and that this activation did not depend on the release of Wnt ligands. Pharmacological inhibition of the β-catenin or of the phosphoinositide 3-kinase (PI3K) pathways revealed that Igf3 activated β-catenin signaling in a manner involving PI3K to promote the differentiation of Aund to Adiff spermatogonia. This mechanism represents an intriguing example for a pituitary hormone like Fsh using Igf signaling to recruit the evolutionary conserved, local β-catenin signaling pathway to regulate spermatogenesis.
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Affiliation(s)
- Diego Safian
- Reproductive Biology GroupDivision Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology , Faculty of Science, University of Utrecht, Utrecht, The Netherlands
| | - Jan Bogerd
- Reproductive Biology GroupDivision Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology , Faculty of Science, University of Utrecht, Utrecht, The Netherlands
| | - Rüdiger W Schulz
- Reproductive Biology GroupDivision Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology , Faculty of Science, University of Utrecht, Utrecht, The Netherlands
- Reproduction and Developmental Biology GroupInstitute of Marine Research, Nordnes, Bergen, Norway
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Brunt L, Scholpp S. The function of endocytosis in Wnt signaling. Cell Mol Life Sci 2018; 75:785-795. [PMID: 28913633 PMCID: PMC5809524 DOI: 10.1007/s00018-017-2654-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 08/17/2017] [Accepted: 09/06/2017] [Indexed: 10/31/2022]
Abstract
Wnt growth factors regulate one of the most important signaling networks during development, tissue homeostasis and disease. Despite the biological importance of Wnt signaling, the mechanism of endocytosis during this process is ill described. Wnt molecules can act as paracrine signals, which are secreted from the producing cells and transported through neighboring tissue to activate signaling in target cells. Endocytosis of the ligand is important at several stages of action: One central function of endocytic trafficking in the Wnt pathway occurs in the source cell. Furthermore, the β-catenin-dependent Wnt ligands require endocytosis for signal activation and to regulate gene transcription in the responding cells. Alternatively, Wnt/β-catenin-independent signaling regulates endocytosis of cell adherence plaques to control cell migration. In this comparative review, we elucidate these three fundamental interconnected functions, which together regulate cellular fate and cellular behavior. Based on established hypotheses and recent findings, we develop a revised picture for the complex function of endocytosis in the Wnt signaling network.
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Affiliation(s)
- Lucy Brunt
- Living Systems Institute, School of Biosciences, College of Life and Environmental Science, University of Exeter, Exeter, EX4 4QD, UK
| | - Steffen Scholpp
- Living Systems Institute, School of Biosciences, College of Life and Environmental Science, University of Exeter, Exeter, EX4 4QD, UK.
- Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
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van Doeselaar S, Burgering BMT. FOXOs Maintaining the Equilibrium for Better or for Worse. Curr Top Dev Biol 2018; 127:49-103. [PMID: 29433740 DOI: 10.1016/bs.ctdb.2017.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
A paradigm shift is emerging within the FOXO field and accumulating evidence indicates that we need to reappreciate the role of FOXOs, at least in cancer development. Here, we discuss the possibility that FOXOs are both tumor suppressors as well as promoters of tumor progression. This is mostly dependent on the biological context. Critical to this dichotomous role is the notion that FOXOs are central in preserving cellular homeostasis in redox control, genomic stability, and protein turnover. From this perspective, a paradoxical role in both suppressing and enhancing tumor progression can be reconciled. As many small molecules targeting the PI3K pathway are developed by big pharmaceutical companies and/or are in clinical trial, we will discuss what the consequences may be for the context-dependent role of FOXOs in tumor development in treatment options based on active PI3K signaling in tumors.
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Affiliation(s)
- Sabina van Doeselaar
- Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Boudewijn M T Burgering
- Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
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29
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Solberg NT, Waaler J, Lund K, Mygland L, Olsen PA, Krauss S. TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer. Mol Cancer Res 2017; 16:543-553. [DOI: 10.1158/1541-7786.mcr-17-0362] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 09/30/2017] [Accepted: 11/10/2017] [Indexed: 11/16/2022]
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30
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Jordán-Álvarez S, Santana E, Casas-Tintó S, Acebes Á, Ferrús A. The equilibrium between antagonistic signaling pathways determines the number of synapses in Drosophila. PLoS One 2017; 12:e0184238. [PMID: 28892511 PMCID: PMC5593197 DOI: 10.1371/journal.pone.0184238] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 08/21/2017] [Indexed: 12/12/2022] Open
Abstract
The number of synapses is a major determinant of behavior and many neural diseases exhibit deviations in that number. However, how signaling pathways control this number is still poorly understood. Using the Drosophila larval neuromuscular junction, we show here a PI3K-dependent pathway for synaptogenesis which is functionally connected with other previously known elements including the Wit receptor, its ligand Gbb, and the MAPkinases cascade. Based on epistasis assays, we determined the functional hierarchy within the pathway. Wit seems to trigger signaling through PI3K, and Ras85D also contributes to the initiation of synaptogenesis. However, contrary to other signaling pathways, PI3K does not require Ras85D binding in the context of synaptogenesis. In addition to the MAPK cascade, Bsk/JNK undergoes regulation by Puc and Ras85D which results in a narrow range of activity of this kinase to determine normalcy of synapse number. The transcriptional readout of the synaptogenesis pathway involves the Fos/Jun complex and the repressor Cic. In addition, we identified an antagonistic pathway that uses the transcription factors Mad and Medea and the microRNA bantam to down-regulate key elements of the pro-synaptogenesis pathway. Like its counterpart, the anti-synaptogenesis signaling uses small GTPases and MAPKs including Ras64B, Ras-like-a, p38a and Licorne. Bantam downregulates the pro-synaptogenesis factors PI3K, Hiw, Ras85D and Bsk, but not AKT. AKT, however, can suppress Mad which, in conjunction with the reported suppression of Mad by Hiw, closes the mutual regulation between both pathways. Thus, the number of synapses seems to result from the balanced output from these two pathways.
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Affiliation(s)
| | | | | | - Ángel Acebes
- Institute Cajal C.S.I.C., Madrid, Spain
- * E-mail: (AF); (AA)
| | - Alberto Ferrús
- Institute Cajal C.S.I.C., Madrid, Spain
- * E-mail: (AF); (AA)
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31
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In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains. Sci Rep 2017; 7:8602. [PMID: 28819213 PMCID: PMC5561119 DOI: 10.1038/s41598-017-09239-5] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 07/19/2017] [Indexed: 12/31/2022] Open
Abstract
Glycogen synthase kinase 3β (GSK3β) is a multifunctional protein kinase involved in many cellular activities including development, differentiation and diseases. GSK3β is thought to be constitutively activated by autophosphorylation at Tyr216 and inactivated by phosphorylation at Ser9. The GSK3β activity has previously been evaluated by inhibitory Ser9 phosphorylation, but it does not necessarily indicate the kinase activity itself. Here, we applied the Phos-tag SDS-PAGE technique to the analysis of GSK3β phosphoisotypes in cells and brains. There were three phosphoisotypes of GSK3β; double phosphorylation at Ser9 and Tyr216, single phosphorylation at Tyr216 and the nonphosphorylated isotype. Active GSK3β with phosphorylation at Tyr216 represented half or more of the total GSK3β in cultured cells. Although levels of phospho-Ser9 were increased by insulin treatment, Ser9 phosphorylation occurred only in a minor fraction of GSK3β. In mouse brains, GSK3β was principally in the active form with little Ser9 phosphorylation, and the phosphoisotypes of GSK3β changed depending on the regions of the brain, age, sex and disease conditions. These results indicate that the Phos-tag SDS-PAGE method provides a simple and appropriate measurement of active GSK3β in vivo, and the activity is regulated by the mechanism other than phosphorylation on Ser9.
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32
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van Kappel EC, Maurice MM. Molecular regulation and pharmacological targeting of the β-catenin destruction complex. Br J Pharmacol 2017. [PMID: 28634996 PMCID: PMC5727331 DOI: 10.1111/bph.13922] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The β‐catenin destruction complex is a dynamic cytosolic multiprotein assembly that provides a key node in Wnt signalling regulation. The core components of the destruction complex comprise the scaffold proteins axin and adenomatous polyposis coli and the Ser/Thr kinases casein kinase 1 and glycogen synthase kinase 3. In unstimulated cells, the destruction complex efficiently drives degradation of the transcriptional coactivator β‐catenin, thereby preventing the activation of the Wnt/β‐catenin pathway. Mutational inactivation of the destruction complex is a major pathway in the pathogenesis of cancer. Here, we review recent insights in the regulation of the β‐catenin destruction complex, including newly identified interaction interfaces, regulatory elements and post‐translationally controlled mechanisms. In addition, we discuss how mutations in core destruction complex components deregulate Wnt signalling via distinct mechanisms and how these findings open up potential therapeutic approaches to restore destruction complex activity in cancer cells. Linked Articles This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc
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Affiliation(s)
- Eline C van Kappel
- Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Madelon M Maurice
- Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
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Hermida MA, Dinesh Kumar J, Leslie NR. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv Biol Regul 2017; 65:5-15. [PMID: 28712664 DOI: 10.1016/j.jbior.2017.06.003] [Citation(s) in RCA: 324] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 06/23/2017] [Indexed: 01/01/2023]
Abstract
Glycogen Synthase Kinase-3 (GSK3 or GSK-3) is a promiscuous protein kinase and its phosphorylation of its diverse substrates has major influences on many areas of physiology and pathology, including cellular metabolism, lineage commitment and neuroscience. GSK3 was one of the first identified substrates of the heavily studied oncogenic kinase AKT, phosphorylation by which inhibits GSK3 activity via the formation of an autoinhibitory pseudosubstrate sequence. This has led to investigation of the role of GSK3 inhibition as a key component of the cellular responses to growth factors and insulin, which stimulate the class I PI 3-Kinases and in turn AKT activity and GSK3 phosphorylation. GSK3 has been shown to phosphorylate several upstream and downstream components of the PI3K/AKT/mTOR signalling network, including AKT itself, RICTOR, TSC1 and 2, PTEN and IRS1 and 2, with the potential to apply feedback control within the network. However, it has been clear for some time that functionally distinct, insulated pools of GSK3 exist which are regulated independently, so that for some GSK3 substrates such as β-catenin, phosphorylation by GSK3 is not controlled by input from PI3K and AKT. Instead, as almost all GSK3 substrates require a priming phosphorylated residue to be 4 amino acids C-terminal to the Ser/Thr phosphorylated by GSK3, the predominant form of regulation of the activity of GSK3 often appears to be through control over these priming events, specific to individual substrates. Therefore, a major role of GSK3 can be viewed as an amplifier of the electrostatic effects on protein function which are caused by these priming phosphorylation events. Here we discuss these different aspects to GSK3 regulation and function, and the functions of GSK3 as it integrates with signalling through the PI3K-AKT-mTOR signalling axis.
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Affiliation(s)
- Miguel A Hermida
- Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot Watt University, Edinburgh EH14 4AS, UK
| | - J Dinesh Kumar
- Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot Watt University, Edinburgh EH14 4AS, UK
| | - Nick R Leslie
- Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot Watt University, Edinburgh EH14 4AS, UK.
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Zhang Z, Wang X, Zhang L, Shi Y, Wang J, Yan H. Wnt/β-catenin signaling pathway in trophoblasts and abnormal activation in preeclampsia (Review). Mol Med Rep 2017; 16:1007-1013. [PMID: 29067442 DOI: 10.3892/mmr.2017.6718] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 03/13/2017] [Indexed: 11/06/2022] Open
Abstract
Preeclampsia (PE) is one of the most common types of hypertensive disease and occurs in 3‑4% of pregnancies. There are a number of theories on the pathogenesis of PE. Abnormal differentiation of the placenta may lead to failure of trophoblast migration, shallow placenta implantation and placental ischemia/hypoxia, followed by the subsequent occurrence of PE. The Wnt/β-catenin pathway is a canonical Wnt‑signaling pathway that regulates several biological processes, including proliferation, migration, invasion and apoptosis. Abnormal activation of the Wnt/β‑catenin signaling pathway may serve an important role in the pathogenesis of various human diseases, particularly in human cancer. Recent studies have demonstrated that the dysregulation of the Wnt/β‑catenin signaling pathway may contribute to PE. The present review aims to summarize the articles on Wnt/β‑catenin signaling pathway in the trophoblast and abnormal activation in PE. Wnt/β-catenin signaling may serve a significant role in the pathogenesis of PE and may be a prospective therapeutic target for the prevention and treatment of PE.
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Affiliation(s)
- Zhan Zhang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xiaofang Wang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Linlin Zhang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ying Shi
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jinming Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Huan Yan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Chen Y, Hu Y, Yang L, Zhou J, Tang Y, Zheng L, Qin P. Runx2 alleviates high glucose-suppressed osteogenic differentiation via PI3K/AKT/GSK3β/β-catenin pathway. Cell Biol Int 2017; 41:822-832. [PMID: 28462510 DOI: 10.1002/cbin.10779] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 04/23/2017] [Indexed: 01/18/2023]
Abstract
Hyperglycemia is one of the most important pathogenesis of diabetic osteopathy. Several lines of studies indicate Runx2 plays a critical role in the process of osteogenic differentiation. However, little studies have analyzed the effect of Runx2 on osteoblast differentiation of rat bone mesenchymal stem cells (rBMSCs) in high-glucose condition. In this study, the effect of Runx2 on osteoblast differentiation in high-glucose condition was evaluated by the expression of osteogenesis-related maker including Runx2, ALP, OC, and OPN, as well as ALP staining, ALP activity, and Alizarin red S staining. Western blot analysis was performed to detect the protein expression levels of p-AKT, AKT, p-GSK3β, GSK3β, and β-catenin. Immunofluorescence staining analysis was performed to detect subcellular localization of β-catenin. Our results revealed that high glucose significantly inhibited osteogenic differentiation, hyperosmolarity did not cause a suppression. In addition, Runx2 could upregulate the expression of osteogenic-related genes and increase matrix mineralization, while applying 10 µM PI3K/AKT inhibitor LY294002 abolished the beneficial effect. Collectively, these results indicate that Runx2 alleviates high glucose-induced inhibition of osteoblast differentiation by modulating PI3K/AKT/GSK3β/β-catenin pathway.
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Affiliation(s)
- Yang Chen
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Yun Hu
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Lan Yang
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Jie Zhou
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Yuying Tang
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Leilei Zheng
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
| | - Pu Qin
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, China
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Persad A, Venkateswaran G, Hao L, Garcia ME, Yoon J, Sidhu J, Persad S. Active β-catenin is regulated by the PTEN/PI3 kinase pathway: a role for protein phosphatase PP2A. Genes Cancer 2017; 7:368-382. [PMID: 28191283 PMCID: PMC5302038 DOI: 10.18632/genesandcancer.128] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Dysregulation of Wnt/β-catenin signaling has been associated with the development and progression of many cancers. The stability and subcellular localization of β-catenin, a dual functional protein that plays a role in intracellular adhesion and in regulating gene expression, is tightly regulated. However, little is known about the transcriptionally active form of β-catenin, Active Beta Catenin (ABC), that is unphosphorylated at serine 37 (Ser37) and threonine 41 (Thr41). Elucidating the mechanism by which β-catenin is activated to generate ABC is vital to the development of therapeutic strategies to block β-catenin signaling for cancer treatment. Using melanoma, breast and prostate cancer cell lines, we show that while cellular β-catenin levels are regulated by the Wnt pathway, cellular ABC levels are mainly regulated by the PI3K pathway and are dependent on the phosphatase activity of the protein phosphatase PP2A. Furthermore, we demonstrate that although the PI3K/PTEN pathway does not regulate total β-catenin protein levels within the cell, it plays a role in regulating the subcellular localization of β-catenin. Our results support a novel functional interaction/cross-talk between the PTEN/PI3K and Wnt pathways in the regulation of the subcellular/nuclear levels of ABC, which is crucially important for the protein's activity as a transcription factor and its biological effects in health and disease.
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Affiliation(s)
- Amit Persad
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | | | - Li Hao
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Maria E Garcia
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Jenny Yoon
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Jaskiran Sidhu
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Sujata Persad
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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Cao J, Tyburczy ME, Moss J, Darling TN, Widlund HR, Kwiatkowski DJ. Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation. J Clin Invest 2016; 127:349-364. [PMID: 27918305 DOI: 10.1172/jci84262] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 10/20/2016] [Indexed: 12/20/2022] Open
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regulator of mTOR complex 1 (mTORC1). Patients with TSC develop hypomelanotic macules (white spots), but the molecular mechanisms underlying their formation are not fully characterized. Using human primary melanocytes and a highly pigmented melanoma cell line, we demonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activation, which results in hyperactivation of glycogen synthase kinase 3β (GSK3β), followed by phosphorylation of and loss of β-catenin from the nucleus, thereby reducing expression of microphthalmia-associated transcription factor (MITF), and subsequent reductions in tyrosinase and other genes required for melanogenesis. Genetic suppression or pharmacological inhibition of this signaling cascade at multiple levels restored pigmentation. Importantly, primary melanocytes isolated from hypomelanotic macules from 6 patients with TSC all exhibited reduced TSC2 protein expression, and 1 culture showed biallelic mutation in TSC2, one of which was germline and the second acquired in the melanocytes of the hypomelanotic macule. These findings indicate that the TSC/mTORC1/AKT/GSK3β/β-catenin/MITF axis plays a central role in regulating melanogenesis. Interventions that enhance or diminish mTORC1 activity or other nodes in this pathway in melanocytes could potentially modulate pigment production.
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Kim JG, Kim MJ, Choi WJ, Moon MY, Kim HJ, Lee JY, Kim J, Kim SC, Kang SG, Seo GY, Kim PH, Park JB. Wnt3A Induces GSK-3β Phosphorylation and β-Catenin Accumulation Through RhoA/ROCK. J Cell Physiol 2016; 232:1104-1113. [DOI: 10.1002/jcp.25572] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 08/29/2016] [Indexed: 12/18/2022]
Affiliation(s)
- Jae-Gyu Kim
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
| | - Myoung-Ju Kim
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
| | - Won-Ji Choi
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
| | - Mi-Young Moon
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
| | - Hee-Jun Kim
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
| | - Jae-Yong Lee
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
- Institute of Cell Differentiation and Aging; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
| | - Jaebong Kim
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
- Institute of Cell Differentiation and Aging; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
| | - Sung-Chan Kim
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
- Institute of Cell Differentiation and Aging; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
| | - Seung Goo Kang
- Division of Biomedical Convergence; School of Biomedical Science and Institute of Bioscience and Biotechnology; Kangwon National University; Chuncheon Kangwon-do Republic of Korea
| | - Goo-Young Seo
- Department of Molecular Bioscience; School of Biomedical Science and Institute of Bioscience and Biotechnology; Kangwon National University; Chuncheon Kangwon-do Republic of Korea
| | - Pyeung-Hyeun Kim
- Department of Molecular Bioscience; School of Biomedical Science and Institute of Bioscience and Biotechnology; Kangwon National University; Chuncheon Kangwon-do Republic of Korea
| | - Jae-Bong Park
- Department of Biochemistry; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
- Institute of Cell Differentiation and Aging; Hallym University College of Medicine; Chuncheon Kangwon-do Republic of Korea
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Xanthatin anti-tumor cytotoxicity is mediated via glycogen synthase kinase-3β and β-catenin. Biochem Pharmacol 2016; 115:18-27. [DOI: 10.1016/j.bcp.2016.06.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 06/15/2016] [Indexed: 12/13/2022]
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Isla AG, Vázquez-Cuevas FG, Peña-Ortega F. Exercise Prevents Amyloid-β-Induced Hippocampal Network Disruption by Inhibiting GSK3β Activation. J Alzheimers Dis 2016; 52:333-43. [DOI: 10.3233/jad-150352] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Arturo G. Isla
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, México
| | | | - Fernando Peña-Ortega
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, México
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Pardo M, Abrial E, Jope RS, Beurel E. GSK3β isoform-selective regulation of depression, memory and hippocampal cell proliferation. GENES BRAIN AND BEHAVIOR 2016; 15:348-55. [PMID: 26749572 DOI: 10.1111/gbb.12283] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Revised: 01/05/2016] [Accepted: 01/05/2016] [Indexed: 01/10/2023]
Abstract
Abnormally active glycogen synthase kinase-3 (GSK3) contributes to pathological processes in multiple psychiatric and neurological disorders. Modeled in mice, this includes increasing susceptibility to dysregulation of mood-relevant behaviors, impairing performance in several cognitive tasks and impairing adult hippocampal neural precursor cell (NPC) proliferation. These deficits are all evident in GSK3α/β knockin mice, in which serine-to-alanine mutations block the inhibitory serine phosphorylation regulation of both GSK3 isoforms, leaving GSK3 hyperactive. It was unknown if both GSK3 isoforms perform redundant actions in these processes, or if hyperactivity of one GSK3 isoform has a predominant effect. To test this, we examined GSK3α or GSK3β knockin mice in which only one isoform was mutated to a hyperactive form. Only GSK3β, not GSK3α, knockin mice displayed heightened vulnerability to the learned helplessness model of depression-like behavior. Three cognitive measures impaired in GSK3α/β knockin mice showed differential regulation by GSK3 isoforms. Novel object recognition was impaired in GSK3β, not in GSK3α, knockin mice, whereas temporal order memory was not impaired in GSK3α or GSK3β knockin mice, and co-ordinate spatial processing was impaired in both GSK3α and GSK3β knockin mice. Adult hippocampal NPC proliferation was severely impaired in GSK3β knockin mice, but not impaired in GSK3α knockin mice. Increased activity of GSK3β, in the absence of overexpression or disease pathology, is sufficient to impair mood regulation, novel object recognition and hippocampal NPC proliferation, whereas hyperactive GSK3α individually does not impair these processes. These results show that hyperactivity of the two GSK3 isoforms execute non-redundant effects on these processes.
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Affiliation(s)
- M Pardo
- Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - E Abrial
- Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - R S Jope
- Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - E Beurel
- Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
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Apocynin and Diphenyleneiodonium Induce Oxidative Stress and Modulate PI3K/Akt and MAPK/Erk Activity in Mouse Embryonic Stem Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:7409196. [PMID: 26788250 PMCID: PMC4691611 DOI: 10.1155/2016/7409196] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 09/13/2015] [Indexed: 01/06/2023]
Abstract
Reactive oxygen species (ROS) are important regulators of cellular functions. In embryonic stem cells, ROS are suggested to influence differentiation status. Regulated ROS formation is catalyzed primarily by NADPH-dependent oxidases (NOXs). Apocynin and diphenyleneiodonium are frequently used inhibitors of NOXs; however, both exhibit uncharacterized effects not related to NOXs inhibition. Interestingly, in our model of mouse embryonic stem cells we demonstrate low expression of NOXs. Therefore we aimed to clarify potential side effects of these drugs. Both apocynin and diphenyleneiodonium impaired proliferation of cells. Surprisingly, we observed prooxidant activity of these drugs determined by hydroethidine. Further, we revealed that apocynin inhibits PI3K/Akt pathway with its downstream transcriptional factor Nanog. Opposite to this, apocynin augmented activity of canonical Wnt signaling. On the contrary, diphenyleneiodonium activated both PI3K/Akt and Erk signaling pathways without affecting Wnt. Our data indicates limits and possible unexpected interactions of NOXs inhibitors with intracellular signaling pathways.
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Regmi SC, Park SY, Kim SJ, Banskota S, Shah S, Kim DH, Kim JA. The Anti-Tumor Activity of Succinyl Macrolactin A Is Mediated through the β-Catenin Destruction Complex via the Suppression of Tankyrase and PI3K/Akt. PLoS One 2015; 10:e0141753. [PMID: 26544726 PMCID: PMC4636297 DOI: 10.1371/journal.pone.0141753] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 10/13/2015] [Indexed: 12/28/2022] Open
Abstract
Accumulated gene mutations in cancer suggest that multi-targeted suppression of affected signaling networks is a promising strategy for cancer treatment. In the present study, we report that 7-O-succinyl macrolactin A (SMA) suppresses tumor growth by stabilizing the β-catenin destruction complex, which was achieved through inhibition of regulatory components associated with the complex. SMA significantly reduced the activities of PI3K/Akt, which corresponded with a decrease in GSK3β phosphorylation, an increase in β-catenin phosphorylation, and a reduction in nuclear β-catenin content in HT29 human colon cancer cells. At the same time, the activity of tankyrase, which inhibits the β-catenin destruction complex by destabilizing the axin level, was suppressed by SMA. Despite the low potency of SMA against tankyrase activity (IC50 of 50.1 μM and 15.5 μM for tankyrase 1 and 2, respectively) compared to XAV939 (IC50 of 11 nM for tankyrase 1), a selective and potent tankyrase inhibitor, SMA had strong inhibitory effects on β-catenin-dependent TCF/LEF1 transcriptional activity (IC50 of 39.8 nM), which were similar to that of XAV939 (IC50 of 28.1 nM). In addition to suppressing the colony forming ability of colon cancer cells in vitro, SMA significantly inhibited tumor growth in CT26 syngenic and HT29 xenograft mouse tumor models. Furthermore, treating mice with SMA in combination with 5-FU in a colon cancer xenograft model or with cisplatin in an A549 lung cancer xenograft model resulted in greater anti-tumor activity than did treatment with the drugs alone. In the xenograft tumor tissues, SMA dose-dependently inhibited nuclear β-catenin along with reductions in GSK3β phosphorylation and increases in axin levels. These results suggest that SMA is a possible candidate as an effective anti-cancer agent alone or in combination with cytotoxic chemotherapeutic drugs, such as 5-FU and cisplatin, and that the mode of action for SMA involves stabilization of the β-catenin destruction complex through inhibition of tankyrase and the PI3K/Akt signaling pathway.
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Affiliation(s)
- Sushil C Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Su Young Park
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Seung Joo Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Suhrid Banskota
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Sajita Shah
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Dong-Hee Kim
- Research and Development Center, Daewoo Pharm. Co. Ltd, Busan, Republic of Korea
| | - Jung-Ae Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
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Applegate CC, Lane MA. Role of retinoids in the prevention and treatment of colorectal cancer. World J Gastrointest Oncol 2015; 7:184-203. [PMID: 26483874 PMCID: PMC4606174 DOI: 10.4251/wjgo.v7.i10.184] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/10/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
Vitamin A and its derivatives, retinoids, have been widely studied for their use as cancer chemotherapeutic agents. With respect to colorectal cancer (CRC), several critical mutations dysregulate pathways implicated in progression and metastasis, resulting in aberrant Wnt/β-catenin signaling, gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt, cyclooxygenase-2 over-expression, reduction of peroxisome proliferator-activated receptor γ activation, and loss of p53 function. Dysregulation leads to increased cellular proliferation and invasion and decreased cell-cell interaction and differentiation. Retinoids affect these pathways by various mechanisms, many involving retinoic acid receptors (RAR). RAR bind to all-trans-retinoic acid (ATRA) to induce the transcription of genes responsible for cellular differentiation. Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation, increase differentiation, or promote apoptosis; as CRC progresses, RAR expression is often lost, rendering treatment of CRCs with ATRA ineffective. Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways. This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR-dependent and RAR-independent mechanisms.
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45
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Chen W, Xu WH. Expression analysis of GSK-3β in diapause pupal brains in the cotton bollworm, Helicoverpa armigera. INSECT SCIENCE 2015; 22:597-605. [PMID: 25772018 DOI: 10.1111/1744-7917.12215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/15/2015] [Indexed: 06/04/2023]
Abstract
Diapause is an adaptive response to adverse environmental conditions, but the molecular mechanisms are unclear. Some signaling molecules have been identified in the regulation of diapause. GSK-3β is an important signaling protein involved in several signaling pathways. In this study, GSK-3β from the cotton bollworm, Helicoverpa armigera, was cloned using reverse transcription polymerase chain reaction and rapid amplification of complementary DNA (cDNA) ends techniques. Sequence analysis showed that the full-length cDNA was 1447 bp containing a 292 bp 5'-untranslated region (UTR), a 162 bp 3'-UTR and a 993 bp open reading frame (ORF). The deduced Har-GSK-3β protein has high identity to other known GSK-3β, as determined by Basic Local Alignment Search Tool analysis. Developmental expression of total GSK-3β and p-GSK-3β (Ser9) in diapause and non-diapause pupal brains was investigated by Western blotting. Results indicated that the activity of GSK-3β is down-regulated in diapause pupal brains, which is further confirmed by Western blotting after diapause break. These finding suggest that the down-regulation of Har-GSK-3β activity may be important for pupal diapause.
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Affiliation(s)
- Wei Chen
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University
| | - Wei-Hua Xu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
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46
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Shen SM, Guo M, Xiong Z, Yu Y, Zhao XY, Zhang FF, Chen GQ. AIF inhibits tumor metastasis by protecting PTEN from oxidation. EMBO Rep 2015; 16:1563-80. [PMID: 26415504 PMCID: PMC4641507 DOI: 10.15252/embr.201540536] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 08/26/2015] [Indexed: 12/27/2022] Open
Abstract
Apoptosis-inducing factor (AIF) exerts dual roles on cell death and survival, but its substrates as a putative oxidoreductase and roles in tumorigenesis remain elusive. Here, we report that AIF physically interacts with and inhibits the oxidation of phosphatase and tensin homolog on chromosome ten (PTEN), a tumor suppressor susceptible for oxidation-mediated inactivation. More intriguingly, we also identify PTEN as a mitochondrial protein and the ectopic expression of mitochondrial targeting sequence-carrying PTEN almost completely inhibits Akt phosphorylation in PTEN-deficient cells. AIF knockdown causes oxidation-mediated inactivation of the lipid phosphatase activity of PTEN, with ensuing activation of Akt kinase, phosphorylation of the Akt substrate GSK-3β, and activation of β-catenin signaling in cancer cells. Through its effect on β-catenin signaling, AIF inhibits epithelial–mesenchymal transition (EMT) and metastasis of cancer cells in vitro and in orthotopically implanted xenografts. Accordingly, the expression of AIF is correlated with the survival of human patients with cancers of multiple origins. These results identify PTEN as the substrate of AIF oxidoreductase and reveal a novel function for AIF in controlling tumor metastasis.
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Affiliation(s)
- Shao-Ming Shen
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Meng Guo
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Zhong Xiong
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Yun Yu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Xu-Yun Zhao
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Fei-Fei Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Guo-Qiang Chen
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-SJTU-SM, Shanghai, China
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Timmermans-Sprang EPM, Gracanin A, Mol JA. High basal Wnt signaling is further induced by PI3K/mTor inhibition but sensitive to cSRC inhibition in mammary carcinoma cell lines with HER2/3 overexpression. BMC Cancer 2015. [PMID: 26205886 PMCID: PMC4513708 DOI: 10.1186/s12885-015-1544-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Elevated basal, ligand-independent, Wnt signaling in some canine breast cancer cells is not caused by classical mutations in APC, β-Catenin or GSK3β but, at least partially, by enhanced LEF1 expression. We examined the expression and function of EGFR/HER-regulated pathways on the ligand-independent Wnt signaling. Methods Twelve canine mammary tumor cell lines with previously reported differential basal Wnt activity were used. The expression levels of genes related to EGF-signaling were analyzed by cluster analysis. Cell lines with a combined overexpression of EGF-related genes and enhanced basal Wnt activity were treated with PI3K/mTor or cSRC inhibitors or transfected with a construct expressing wild-type PTEN. Subsequently, effects were measured on Wnt activity, cell proliferation, gene expression and protein level. Results High basal Wnt/LEF1 activity was associated with overexpression of HER2/3, ID1, ID2, RAC1 and HSP90 together with low to absent cMET and PTEN mRNA expression, suggesting a connection between Wnt- and HER-signaling pathways. Inhibition of the HER-regulated PI3K/mTor pathway using the dual PI3K/mTor inhibitor BEZ235 or the mTor inhibitor Everolimus® resulted in reduced cell proliferation. In the cell line with high basal Wnt activity, however, an unexpected further increased Wnt activity was found that could be greatly reduced after inhibition of the HER-regulated cSRC activity. Inhibition of the PI3K/mTor pathway was associated with enhanced expression of β-Catenin, Axin2, MUC1, cMET, EGFR and HER2 and a somewhat increased β-Catenin protein content, whereas cSRC inhibition was associated with slightly enhanced HER3 and SLUG mRNA expression. A high protein expression of HER3 was found only in a cell line with high basal Wnt activity. Conclusions High basal Wnt activity in some mammary cancer cell lines is associated with overexpression of HER-receptor related genes and HER3 protein, and the absence of PTEN. Inhibition of the PI3K/mTor pathway further stimulated, however, canonical Wnt signaling, whereas the inhibitory effect with the cSRC inhibitor Src-I1 on the Wnt activity further suggested a connection between Wnt and HER2/3-signaling.
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Affiliation(s)
- Elpetra P M Timmermans-Sprang
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584, CM, Utrecht, The Netherlands.
| | - Ana Gracanin
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584, CM, Utrecht, The Netherlands.
| | - Jan A Mol
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584, CM, Utrecht, The Netherlands.
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Li Q, Li Y, Gu B, Fang L, Zhou P, Bao S, Huang L, Dai X. Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation. J Biol Chem 2015; 290:21553-67. [PMID: 26170450 DOI: 10.1074/jbc.m115.639419] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Indexed: 01/16/2023] Open
Abstract
Pygopus 2 (Pygo2/PYGO2) is an evolutionarily conserved coactivator and chromatin effector in the Wnt/β-catenin signaling pathway that regulates cell growth and differentiation in various normal and malignant tissues. Although PYGO2 is highly overexpressed in a number of human cancers, the molecular mechanism underlying its deregulation is largely unknown. Here we report that Pygo2 protein is degraded through the ubiquitin/proteasome pathway and is posttranslationally stabilized through phosphorylation by activated phosphatidylinositol 3-kinase/Akt signaling. Specifically, Pygo2 is stabilized upon inhibition of the proteasome, and its intracellular level is regulated by Cullin 4 (Cul4) and DNA damage-binding protein 1 (DDB1), components of the Cul4-DDB1 E3 ubiquitin ligase complex. Furthermore, Pygo2 is phosphorylated at multiple residues, and Akt-mediated phosphorylation at serine 48 leads to its decreased ubiquitylation and increased stability. Finally, we provide evidence that Akt and its upstream growth factors act in parallel with Wnt to stabilize Pygo2. Taken together, our findings highlight chromatin regulator Pygo2 as a common node downstream of oncogenic Wnt and Akt signaling pathways and underscore posttranslational modification, particularly phosphorylation and ubiquitylation, as a significant mode of regulation of Pygo2 protein expression.
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Affiliation(s)
- Qiuling Li
- From the Department of Biological Chemistry, the State Key Laboratory of Molecular and Developmental Biology, Center for Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, and
| | - Yuewei Li
- the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065
| | - Bingnan Gu
- From the Department of Biological Chemistry
| | - Lei Fang
- Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California 92697
| | - Pengbo Zhou
- the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065
| | - Shilai Bao
- the State Key Laboratory of Molecular and Developmental Biology, Center for Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, and
| | - Lan Huang
- Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California 92697,
| | - Xing Dai
- From the Department of Biological Chemistry,
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Li B, Thrasher JB, Terranova P. Glycogen synthase kinase-3: a potential preventive target for prostate cancer management. Urol Oncol 2015; 33:456-63. [PMID: 26051358 DOI: 10.1016/j.urolonc.2015.05.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/30/2015] [Accepted: 05/05/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Prostate cancers are the frequently diagnosed cancers in men, and patients with metastatic disease only have 28% chance for 5-year survival. Patients with low-risk tumors are subjected to active surveillance, whereas high-risk cases are actively treated. Unfortunately, there is no cure for patients with late-stage disease. Glycogen synthase kinase-3 (GSK-3, α and β) is a protein serine/threonine kinase and has diverse cellular functions and numerous substrates. We sought to summarize all the studies done with GSK-3 in prostate cancers and to provide a prospective direction for future work. METHODS AND MATERIALS A comprehensive search of the literature on the electronic databases PubMed was conducted for the subject terms of GSK-3 and prostate cancer. Gene mutation and expression information was extracted from Oncomine and COSMIC databases. Case reports were not included. RESULTS Accumulating evidence indicates that GSK-3α is mainly expressed in low-risk prostate cancers and is related to hormone-dependent androgen receptor (AR)-mediated gene expression, whereas GSK-3β is mainly expressed in high-risk prostate cancers and is related to hormone-independent AR-mediated gene expression. GSK-3 has been demonstrated as a positive regulator in AR transactivation and prostate cancer growth independent of the Wnt/β-catenin pathway. Different types of GSK-3inhibitors including lithium show promising results in suppressing tumor growth in different animal models of prostate cancer. Importantly, clinical use of lithium is associated with reduced cancer incidence in psychiatric patients. CONCLUSIONS Taken together, GSK-3 inhibition might be implicated in prostate cancer management as a preventive treatment.
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Affiliation(s)
- Benyi Li
- Department of Urology, University of Kansas Medical Center, Kansas City, KS.
| | | | - Paul Terranova
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS; Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS
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Cuesto G, Jordán-Álvarez S, Enriquez-Barreto L, Ferrús A, Morales M, Acebes Á. GSK3β inhibition promotes synaptogenesis in Drosophila and mammalian neurons. PLoS One 2015; 10:e0118475. [PMID: 25764078 PMCID: PMC4357437 DOI: 10.1371/journal.pone.0118475] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 01/17/2015] [Indexed: 01/22/2023] Open
Abstract
The PI3K-dependent activation of AKT results in the inhibition of GSK3β in most signaling pathways. These kinases regulate multiple neuronal processes including the control of synapse number as shown for Drosophila and rodents. Alzheimer disease's patients exhibit high levels of circulating GSK3β and, consequently, pharmacological strategies based on GSK3β antagonists have been designed. The approach, however, has yielded inconclusive results so far. Here, we carried out a comparative study in Drosophila and rats addressing the role of GSK3β in synaptogenesis. In flies, the genetic inhibition of the shaggy-encoded GSK3β increases the number of synapses, while its upregulation leads to synapse loss. Likewise, in three weeks cultured rat hippocampal neurons, the pharmacological inhibition of GSK3β increases synapse density and Synapsin expression. However, experiments on younger cultures (12 days) yielded an opposite effect, a reduction of synapse density. This unexpected finding seems to unveil an age- and dosage-dependent differential response of mammalian neurons to the stimulation/inhibition of GSK3β, a feature that must be considered in the context of human adult neurogenesis and pharmacological treatments for Alzheimer's disease based on GSK3β antagonists.
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Affiliation(s)
- Germán Cuesto
- Structural Synaptic Plasticity Laboratory, Department of Neurodegenerative Diseases, Centro de Investigación Biomédica de La Rioja, Logroño, La Rioja, Spain
| | - Sheila Jordán-Álvarez
- Department of Cellular, Molecular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Lilian Enriquez-Barreto
- Structural Synaptic Plasticity Laboratory, Department of Neurodegenerative Diseases, Centro de Investigación Biomédica de La Rioja, Logroño, La Rioja, Spain
| | - Alberto Ferrús
- Department of Cellular, Molecular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Miguel Morales
- Structural Synaptic Plasticity Laboratory, Department of Neurodegenerative Diseases, Centro de Investigación Biomédica de La Rioja, Logroño, La Rioja, Spain
- * E-mail: (AA); (MM)
| | - Ángel Acebes
- Department of Cellular, Molecular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain
- * E-mail: (AA); (MM)
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