Role of Glycogen Synthase Kinase-3 in Cell Fate and Epithelial-Mesenchymal Transitions

Glycogen synthase kinase-3 (GSK3) is a highly conserved protein kinase that is involved in several important cell signaling pathways and is associated with a range of medical conditions. Previous studies indicated a major role of the Dictyostelium homologue of GSK3 (gskA) in cell fate determination during morphogenesis of the fruiting body; however, transcriptomic and proteomic studies have suggested that GSK3 regulates gene expression much earlier during Dictyostelium development. To investigate a potential earlier role of GskA, we examined the effects of loss of gskA on cell aggregation. We find that cells lacking gskA exhibit poor chemotaxis toward cAMP and folate. Mutants fail to activate two important regulatory signaling pathways, mediated by phosphatidylinositol 3,4,5-trisphosphate (PIP3) and target of rapamycin complex 2 (TORC2), which in combination are required for chemotaxis and cAMP signaling. These results indicate that GskA is required during early stages of Dictyostelium development, in which it is necessary for both chemotaxis and cell signaling.

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The Role of Glycogen Synthase Kinase 3 (GSK3) in Regulating Intracellular Transport

Biophysical Journal ◽

10.1016/j.bpj.2019.11.2425 ◽

2020 ◽

Vol 118 (3) ◽

pp. 431a

Author(s):

Ibtissem Nabti ◽

George T Shubeita

Keyword(s):

Intracellular Transport ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3

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Role of Glycogen Synthase Kinase 3 in regulating Vascular Permeability associated with Asthma

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2006.11.643 ◽

2007 ◽

Vol 119 (1) ◽

pp. S131

Author(s):

Y. Morimoto ◽

N. Goplen ◽

R. Alam

Keyword(s):

Vascular Permeability ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3

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Erratum to: A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3

Biochemistry (Moscow) ◽

10.1134/s0006297921050096 ◽

2021 ◽

Vol 86 (5) ◽

pp. 611-611

Author(s):

Gregory A. Shilovsky ◽

Tatyana S. Putyatina ◽

Galina V. Morgunova ◽

Alexander V. Seliverstov ◽

Vasily V. Ashapkin ◽

...

Keyword(s):

Glycogen Synthase ◽

Dual Role ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3

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Possible Role of the Glycogen Synthase Kinase-3 Signaling Pathway in Trimethyltin-Induced Hippocampal Neurodegeneration in Mice

PLoS ONE ◽

10.1371/journal.pone.0070356 ◽

2013 ◽

Vol 8 (8) ◽

pp. e70356 ◽

Cited By ~ 24

Author(s):

Juhwan Kim ◽

Miyoung Yang ◽

Sung-Ho Kim ◽

Jong-Choon Kim ◽

Hongbing Wang ◽

...

Keyword(s):

Signaling Pathway ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Hippocampal Neurodegeneration

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Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽

10.3390/cells9051120 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1120 ◽

Cited By ~ 1

Author(s):

Manisha Gupte ◽

Prachi Umbarkar ◽

Anand Prakash Singh ◽

Qinkun Zhang ◽

Sultan Tousif ◽

...

Keyword(s):

Glucose Tolerance ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Glycogen Synthase ◽

Critical Role ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Total Period ◽

Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

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Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3

AJP Cell Physiology ◽

10.1152/ajpcell.00061.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. C1289-C1303 ◽

Cited By ~ 5

Author(s):

Mahboubeh S. Noori ◽

Pooja M. Bhatt ◽

Maria C. Courreges ◽

Davoud Ghazanfari ◽

Chaz Cuckler ◽

...

Keyword(s):

Design Space ◽

Potent Inhibitor ◽

Glycogen Synthase ◽

Selective Inhibition ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Cellular Functions ◽

Starting Point ◽

Potential Therapeutics

Glycogen synthase kinase-3 (GSK-3) is a multitasking protein kinase that regulates numerous critical cellular functions. Not surprisingly, elevated GSK-3 activity has been implicated in a host of diseases including pathological inflammation, diabetes, cancer, arthritis, asthma, bipolar disorder, and Alzheimer’s. Therefore, reagents that inhibit GSK-3 activity provide a means to investigate the role of GSK-3 in cellular physiology and pathophysiology and could become valuable therapeutics. Finding a potent inhibitor of GSK-3 that can selectively target this kinase, among over 500 protein kinases in the human genome, is a significant challenge. Thus there remains a critical need for the identification of selective inhibitors of GSK-3. In this work, we introduce a novel small organic compound, namely COB-187, which exhibits potent and highly selective inhibition of GSK-3. Specifically, this study 1) utilized a molecular screen of 414 kinase assays, representing 404 unique kinases, to reveal that COB-187 is a highly potent and selective inhibitor of GSK-3; 2) utilized a cellular assay to reveal that COB-187 decreases the phosphorylation of canonical GSK-3 substrates indicating that COB-187 inhibits cellular GSK-3 activity; and 3) reveals that a close isomer of COB-187 is also a selective and potent inhibitor of GSK-3. Taken together, these results demonstrate that we have discovered a region of chemical design space that contains novel GSK-3 inhibitors. These inhibitors will help to elucidate the intricate function of GSK-3 and can serve as a starting point for the development of potential therapeutics for diseases that involve aberrant GSK-3 activity.

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