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Cells
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Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy
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Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 30672

Special Issue Editor

Prof. Hagit Eldar-Finkelman

E-Mail Website
Guest Editor
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Interests: cell signaling; protein kinases; drug design and developemnt; neurodegeneration

Special Issue Information

Dear Colleagues,

Research in the glycogen synthase kinase-3 (GSK-3) arena  is an inspiring example of scientific curiosity, twists in concepts, and unexpected surprises. GSK-3 participates in diverse biological processes and plays different roles in different contexts. Yet, it is a promising drug discovery target in treating multiple pathological conditions. Perhaps, the sophisticated mechanises in which GSK-3 is integrated into cellular networks is key in our understanding of the therapeutic benefits achieved with GSK-3 inhibition . Continuous research indeed uncovers new insights that are sometimes surprising of the molecular mechanisms underlying human diseases. The role of GSK-3 in the pathogenies of  diseases such as diabetes, psychiatric disorders and Alzheimer’s disease has been demonstrated, more connections describing GSK-3 with cellular targets and biological resposnes are uncovered in present studies.  Another ‘hot’ topic to be mentioned is the efforts in understanding the (potential) distinguished functions of GSK-3 isozymes, GSK-a and GSK-b, an issue that remains soemwhat elusive. In this Special Issue of Cells, I invite you to contribute, either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy”. Expert articles describing mechanistic, functional, cellular, biochemical, and translational aspects of GSK-3 are highly welcome. Relevant topics include, but are not limited to:

  • GSK-3
  • Protein kinases
  • Cell signaling
  • Wnt signaling
  • Neurodegenerative disorders
  • Psychiatric disorders
  • Development
  • Sperm function
  • Neuron plasticity
  • Stem cell biology
  • Translational medicine
  • Drug discovery
  • Drug design

Prof. Hagit Eldar-Finkelman
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • GSK-3
  • Protein kinases
  • Cell signaling
  • Wnt signaling
  • Neurodegenerative disorders
  • Psychiatric disorders
  • Development
  • Sperm function
  • Neuron plasticity
  • Stem cell biology
  • Translational medicine
  • Drug discovery
  • Drug design

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

3 pages, 189 KiB  
Editorial
Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy
by Sara Arciniegas Ruiz, Ido Rippin and Hagit Eldar-Finkelman
Cells 2022, 11(10), 1618; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101618 - 12 May 2022
Cited by 2 | Viewed by 1108
Abstract
Over the last decade, there has been continuous progress in our understanding of the biology of the protein kinase GSK-3 [...] Full article
(This article belongs to the Special Issue Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy)

Research

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12 pages, 2194 KiB  
Article
Isoform-Specific Role of GSK-3 in High Fat Diet Induced Obesity and Glucose Intolerance
by Manisha Gupte, Sultan Tousif, Jacob J. Lemon, Angelica Toro Cora, Prachi Umbarkar and Hind Lal
Cells 2022, 11(3), 559; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11030559 - 5 Feb 2022
Cited by 8 | Viewed by 2295
Abstract
Obesity-associated metabolic disorders are rising to pandemic proportions; hence, there is an urgent need to identify underlying molecular mechanisms. Glycogen synthase kinase-3 (GSK-3) signaling is highly implicated in metabolic diseases. Furthermore, GSK-3 expression and activity are increased in Type 2 diabetes patients. However, [...] Read more.
Obesity-associated metabolic disorders are rising to pandemic proportions; hence, there is an urgent need to identify underlying molecular mechanisms. Glycogen synthase kinase-3 (GSK-3) signaling is highly implicated in metabolic diseases. Furthermore, GSK-3 expression and activity are increased in Type 2 diabetes patients. However, the isoform-specific role of GSK-3 in obesity and glucose intolerance is unclear. Pharmacological GSK-3 inhibitors are not isoform-specific, and tissue-specific genetic models are of limited value to predict the clinical outcome of systemic inhibiion. To overcome these limitations, we created novel mouse models of ROSA26CreERT2-driven, tamoxifen-inducible conditional deletion of GSK-3 that allowed us to delete the gene globally in an isoform-specific and temporal manner. Isoform-specific GSK-3 KOs and littermate controls were subjected to a 16-week high-fat diet (HFD) protocol. On an HFD, GSK-3α KO mice had a significantly lower body weight and modest improvement in glucose tolerance compared to their littermate controls. In contrast, GSK-3β-deletion-mediated improved glucose tolerance was evident much earlier in the timeline and extended up to 12 weeks post-HFD. However, this protective effect weakened after chronic HFD (16 weeks) when GSK-3β KO mice had a significantly higher body weight compared to controls. Importantly, GSK-3β KO mice on a control diet maintained significant improvement in glucose tolerance even after 16 weeks. In summary, our novel mouse models allowed us to delineate the isoform-specific role of GSK-3 in obesity and glucose tolerance. From a translational perspective, our findings underscore the importance of maintaining a healthy weight in patients receiving lithium therapy, which is thought to work by GSK-3 inhibition mechanisms. Full article
(This article belongs to the Special Issue Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy)
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Review

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19 pages, 594 KiB  
Review
GSK-3 and Tau: A Key Duet in Alzheimer’s Disease
by Carmen Laura Sayas and Jesús Ávila
Cells 2021, 10(4), 721; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040721 - 24 Mar 2021
Cited by 102 | Viewed by 8074
Abstract
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with a plethora of substrates. As a modulator of several cellular processes, GSK-3 has a central position in cell metabolism and signaling, with important roles both in physiological and pathological conditions. GSK-3 has [...] Read more.
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with a plethora of substrates. As a modulator of several cellular processes, GSK-3 has a central position in cell metabolism and signaling, with important roles both in physiological and pathological conditions. GSK-3 has been associated with a number of human disorders, such as neurodegenerative diseases including Alzheimer’s disease (AD). GSK-3 contributes to the hyperphosphorylation of tau protein, the main component of neurofibrillary tangles (NFTs), one of the hallmarks of AD. GSK-3 is further involved in the regulation of different neuronal processes that are dysregulated during AD pathogenesis, such as the generation of amyloid-β (Aβ) peptide or Aβ-induced cell death, axonal transport, cholinergic function, and adult neurogenesis or synaptic function. In this review, we will summarize recent data about GSK-3 involvement in these processes contributing to AD pathology, mostly focusing on the crucial interplay between GSK-3 and tau protein. We further discuss the current development of potential AD therapies targeting GSK-3 or GSK-3-phosphorylated tau. Full article
(This article belongs to the Special Issue Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy)
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21 pages, 1274 KiB  
Review
Mechanisms and Therapeutic Implications of GSK-3 in Treating Neurodegeneration
by Ido Rippin and Hagit Eldar-Finkelman
Cells 2021, 10(2), 262; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020262 - 29 Jan 2021
Cited by 46 | Viewed by 7342
Abstract
Neurodegenerative disorders are spreading worldwide and are one of the greatest threats to public health. There is currently no adequate therapy for these disorders, and therefore there is an urgent need to accelerate the discovery and development of effective treatments. Although neurodegenerative disorders [...] Read more.
Neurodegenerative disorders are spreading worldwide and are one of the greatest threats to public health. There is currently no adequate therapy for these disorders, and therefore there is an urgent need to accelerate the discovery and development of effective treatments. Although neurodegenerative disorders are broad ranging and highly complex, they may share overlapping mechanisms, and thus potentially manifest common targets for therapeutic interventions. Glycogen synthase kinase-3 (GSK-3) is now acknowledged to be a central player in regulating mood behavior, cognitive functions, and neuron viability. Indeed, many targets controlled by GSK-3 are critically involved in progressing neuron deterioration and disease pathogenesis. In this review, we focus on three pathways that represent prominent mechanisms linking GSK-3 with neurodegenerative disorders: cytoskeleton organization, the mammalian target of rapamycin (mTOR)/autophagy axis, and mitochondria. We also consider the challenges and opportunities in the development of GSK-3 inhibitors for treating neurodegeneration. Full article
(This article belongs to the Special Issue Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy)
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24 pages, 1494 KiB  
Review
Lithium and Therapeutic Targeting of GSK-3
by Melinda E. Snitow, Rahul S. Bhansali and Peter S. Klein
Cells 2021, 10(2), 255; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020255 - 28 Jan 2021
Cited by 48 | Viewed by 7527
Abstract
Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently [...] Read more.
Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections. Full article
(This article belongs to the Special Issue Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy)
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12 pages, 1778 KiB  
Review
GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior
by Claire Racaud-Sultan and Nathalie Vergnolle
Cells 2021, 10(2), 225; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020225 - 24 Jan 2021
Cited by 11 | Viewed by 3400
Abstract
In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity [...] Read more.
In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients. Full article
(This article belongs to the Special Issue Prospects in GSK-3 Signaling: From Cellular Regulation to Disease Therapy)
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