Elsevier

Pharmacology & Therapeutics

Volume 148, April 2015, Pages 114-131
Pharmacology & Therapeutics

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

https://doi.org/10.1016/j.pharmthera.2014.11.016Get rights and content

Abstract

Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.

Introduction

Not long ago, glycogen synthase kinase-3 (GSK3) seemed to be a rather curious enzyme in a number of ways, but perhaps not one of especially widespread importance (Grimes and Jope, 2001, Woodgett, 2001). GSK3 was considered of some interest because it has the unconventional characteristics for a kinase of being constitutively active, its substrates usually need to be pre-phosphorylated by another kinase, and it is inhibited, rather than activated, in response to stimulation of the two main signaling pathways known to impinge on GSK3, the insulin and Wnt pathways. These characteristics made GSK3 somewhat idiosyncratic compared with other kinases, but did not engender especially widespread attention. However, two key developments in particular transformed this perspective to the current state of widespread interest. One of these developments was the discovery that GSK3 is a key kinase contributing to abnormal phosphorylation of the microtubule-binding protein tau in the process thought to cause neurofibrillary tangles in Alzheimer's disease (Hanger et al., 1992, Mandelkow et al., 1992). This finding brought GSK3 to the attention of the many investigators, as well as pharmaceutical companies, who were looking for therapeutic targets for Alzheimer's disease. The other development was the finding that GSK3 is inhibited by lithium (Klein and Melton, 1996, Stambolic et al., 1996). Lithium is the classical mood stabilizer used in the treatment of bipolar disorder, so this finding raised the prospect that GSK3 may have a central role in bipolar disorder, and it also provided a relatively selective inhibitor of GSK3 that opened the door for discoveries of other targets of GSK3. Thus, during the last 20 years the interest in GSK3 and its known actions swung to the opposite pole, and it now seems like GSK3 touches almost every aspect of cellular signaling and is involved in an unparalleled number of disease processes.

In conjunction with these discoveries and the ensuing enormous growth in recognizing new actions of GSK3, many additional inhibitors of GSK3 were developed as GSK3 began to be seriously considered as a therapeutic target (Eldar-Finkelman & Martinez, 2011). Potential therapeutic applications include many prevalent conditions, such as cancer, cardiovascular diseases, diabetes, inflammatory conditions, neurodegenerative diseases, and psychiatric diseases, as well as other less prevalent conditions. Such an expansive influence on cellular signaling and association with multiple disease processes has stimulated skeptics to inquire how GSK3 can manage all of its tasks in an organized fashion, and how such a pervasive kinase can reasonably be thought of as a feasible therapeutic target. Although these conundrums remain to be definitively answered, much recent progress reviewed here is leading to a more complete understanding of this enigmatic kinase and its potential as a therapeutic target. Moreover, substantial evidence supports the conclusion that inhibition of GSK3 is an important action contributing to the mood stabilizing action of lithium in bipolar disease, demonstrating that inhibition of GSK3 is, in fact, feasible for safe therapeutic interventions.

A single review cannot adequately cover all aspects concerning GSK3, and there are now excellent reviews available that are focused on many of the individual processes and diseases involving GSK3, which are cited below. Therefore, this review is focused on conceptualizations concerning the actions and regulation of GSK3, on misunderstandings and ambiguities about GSK3, and on new directions that are developing in GSK3 research. Many of these topics are best considered in discussions of the mechanisms regulating GSK3 and its associations with several classes of diseases.

Section snippets

Regulation of glycogen synthase kinase-3-mediated substrate phosphorylation

GSK3 refers to two paralogs that are commonly referred to as isoforms, GSK3α and GSK3β. A theoretical analysis found that GSK3β has more predicted substrates than any other kinase (Linding et al., 2007). The mean number of substrates for the 68 kinases examined was 12, the average was 70 substrates, and the predicted number of substrates for GSK3β was over 500 (Linding et al., 2007). While this is almost certainly an overestimation, about 100 proteins phosphorylated by GSK3 have already been

G protein-coupled receptors

Much excitement has been generated by the rapidly developing concept that GSK3 has regulatory interactions with multiple intracellular receptor-coupled signaling proteins, such as β-arrestin and G-proteins, as well as with several receptors themselves (Fig. 4). Most well-understood is the dopamine D2 receptor signaling mechanism that involves GSK3 and β-arrestin (Beaulieu, Marion, et al., 2008, Beaulieu et al., 2005, Beaulieu et al., 2004). As others have reviewed in detail (Beaulieu et al.,

Differential actions and regulation of glycogen synthase kinase-3α and glycogen synthase kinase-3β

An emerging topic is the identification of differential regulation and actions of GSK3α and GSK3β. The catalytic domains of GSK3α and GSK3β are nearly identical, but their C-terminal sequences diverge and GSK3α contains a large glycine-rich N-terminal region that is absent in GSK3β (Kaidanovich-Beilin & Woodgett, 2011). Although commonly referred to as isoforms, GSK3α and GSK3β are actually paralogs, homologous proteins derived from different genes. It is surprising that little is known about

Targeting glycogen synthase kinase-3 therapeutically

With its demonstrated participation in many signaling pathways associated with disease pathology, it is not surprising that GSK3 is being considered as a therapeutic target in multiple disorders. However, the great number of substrates that are phosphorylated by GSK3 raises the question of whether this limits its feasibility as a therapeutic target because of the potential disruption of many cellular processes. This rational skepticism is countered by the already demonstrated safe and effective

Conclusions

GSK3 has proven to be a kinase so adaptable that it has been recruited evolutionarily to phosphorylate over 100 substrates, empowering it to participate in regulating numerous cellular functions. This flexibility may stem from the multiple sophisticated mechanisms that regulate the actions of GSK3, ensuring that it phosphorylates substrates only at the proper time and in discreet subcellular compartments, often established by protein complexes. Thus, post-translational modifications, substrate

Conflict of interest

The authors have no conflicts of interest.

Acknowledgments

Research in the authors' laboratories was supported by grants from the NIMH (MH038752, MH090236, MH095380).

References (306)

  • F. Benedetti et al.

    Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3β −50 T/C SNP

    Neurosci Lett

    (2005)
  • E. Beurel et al.

    The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways

    Prog Neurobiol

    (2006)
  • E. Beurel et al.

    Differential regulation of STAT family members by glycogen synthase kinase-3

    J Biol Chem

    (2008)
  • E. Beurel et al.

    Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3)

    Trends Immunol

    (2010)
  • G.N. Bijur et al.

    Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3β

    J Biol Chem

    (2001)
  • J. Brognard et al.

    PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms

    Mol Cell

    (2007)
  • C. Charvet et al.

    Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53

    Mol Cell

    (2011)
  • Y. Chen et al.

    Dual phosphorylation of suppressor of fused (Sufu) by PKA and GSK3β regulates its stability and localization in the primary cilium

    J Biol Chem

    (2011)
  • H. Cheng et al.

    Targeting GSK-3 family members in the heart: a very sharp double-edged sword

    J Mol Cell Cardiol

    (2011)
  • J. Cho et al.

    Distinct roles of glycogen synthase kinase (GSK)-3α and GSK-3β in mediating cardiomyocyte differentiation in murine bone marrow-derived mesenchymal stem cells

    J Biol Chem

    (2009)
  • C.H. Choi et al.

    Pharmacological reversal of synaptic plasticity deficits in the mouse model of Fragile X syndrome by group II mGluR antagonist or lithium treatment

    Brain Res

    (2011)
  • A.R. Cole et al.

    GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons

    J Biol Chem

    (2004)
  • S. Cuzzocrea et al.

    Glycogen synthase kinase-3β inhibition attenuates the degree of arthritis caused by type II collagen in the mouse

    Clin Immunol

    (2006)
  • P. De Sarno et al.

    In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors

    Neurobiol Aging

    (2006)
  • P. De Sarno et al.

    Regulation of Akt and glycogen synthase kinase-3β phosphorylation by sodium valproate and lithium

    Neuropharmacology

    (2002)
  • Y. Deng et al.

    β-Amyloid impairs the regulation of N-methyl-d-aspartate receptors by glycogen synthase kinase 3

    Neurobiol Aging

    (2014)
  • A.A. DePaoli-Roach

    Synergistic phosphorylation and activation of ATP-Mg-dependent phosphoprotein phosphatase by F A/GSK-3 and casein kinase II (PC0.7)

    J Biol Chem

    (1984)
  • I. Dewachter et al.

    GSK3β, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at serine-9

    Neurobiol Dis

    (2009)
  • R.S. Duman et al.

    A neurotrophic model for stress-related mood disorders

    Biol Psychiatry

    (2006)
  • H. Eldar-Finkelman et al.

    Substrate competitive GSK-3 inhibitors — strategy and implications

    Biochim Biophys Acta

    (2010)
  • T.Y. Eom et al.

    Blocked inhibitory serine-phosphorylation of glycogen synthase kinase-3α/β impairs in vivo neural precursor cell proliferation

    Biol Psychiatry

    (2009)
  • G. Fan et al.

    Phospholipase C-independent activation of glycogen synthase kinase-3β and C-terminal Src kinase by Gαq

    J Biol Chem

    (2003)
  • D.M. Ferkey et al.

    Glycogen synthase kinase-3β mutagenesis identifies a common binding domain for GBP and Axin

    J Biol Chem

    (2002)
  • T. Force et al.

    Unique and overlapping functions of GSK-3 isoforms in cell differentiation and proliferation and cardiovascular development

    J Biol Chem

    (2009)
  • S. Frame et al.

    A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation

    Mol Cell

    (2001)
  • J. Franca-Koh et al.

    The regulation of glycogen synthase kinase-3 nuclear export by Frat/GBP

    J Biol Chem

    (2002)
  • A.V. Franklin et al.

    Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in Fragile X mice

    Biol Psychiatry

    (2014)
  • E. Fraser et al.

    Identification of the Axin and Frat binding region of glycogen synthase kinase-3

    J Biol Chem

    (2002)
  • S. Amar et al.

    The possible involvement of glycogen synthase kinase-3 (GSK-3) in diabetes, cancer and central nervous system diseases

    Curr Pharm Des

    (2011)
  • J.N. Anastas et al.

    WNT signalling pathways as therapeutic targets in cancer

    Nat Rev Cancer

    (2012)
  • J. Avila et al.

    Role of glycogen synthase kinase-3 in Alzheimer's disease pathogenesis and glycogen synthase kinase-3 inhibitors

    Expert Rev Neurother

    (2010)
  • V. Banerji et al.

    The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia

    J Clin Invest

    (2012)
  • Z. Bao et al.

    Glycogen synthase kinase-3β inhibition attenuates asthma in mice

    Am J Respir Crit Care Med

    (2007)
  • F.H. Bardai et al.

    Selective toxicity by HDAC3 in neurons: regulation by Akt and GSK3β

    J Neurosci

    (2011)
  • J.M. Beaulieu et al.

    Akt/GSK3 signaling in the action of psychotropic drugs

    Annu Rev Pharmacol Toxicol

    (2009)
  • J.M. Beaulieu et al.

    Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

    Proc Natl Acad Sci U S A

    (2004)
  • J.M. Beaulieu et al.

    Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

    Proc Natl Acad Sci U S A

    (2008)
  • M.M. Bellet et al.

    Mammalian circadian clock and metabolism — the epigenetic link

    J Cell Sci

    (2010)
  • E. Berry-Kravis et al.

    Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome

    J Dev Behav Pediatr

    (2008)
  • Y. Bersudsky et al.

    Glycogen synthase kinase-3β heterozygote knockout mice as a model of findings in postmortem schizophrenia brain or as a model of behaviors mimicking lithium action: negative results

    Behav Pharmacol

    (2008)
  • Cited by (1180)

    View all citing articles on Scopus
    View full text