The multifaceted roles of glycogen synthase kinase 3β in cellular signaling

doi:10.1016/S0301-0082(01)00011-9

Progress in Neurobiology

Volume 65, Issue 4, November 2001, Pages 391-426

https://doi.org/10.1016/S0301-0082(01)00011-9 Get rights and content

Abstract

Glycogen synthase kinase-3β (GSK3β) is a fascinating enzyme with an astoundingly diverse number of actions in intracellular signaling systems. GSK3β activity is regulated by serine (inhibitory) and tyrosine (stimulatory) phosphorylation, by protein complex formation, and by its intracellular localization. GSK3β phosphorylates and thereby regulates the functions of many metabolic, signaling, and structural proteins. Notable among the signaling proteins regulated by GSK3β are the many transcription factors, including activator protein-1, cyclic AMP response element binding protein, heat shock factor-1, nuclear factor of activated T cells, Myc, β-catenin, CCAAT/enhancer binding protein, and NFκB. Lithium, the primary therapeutic agent for bipolar mood disorder, is a selective inhibitor of GSK3β. This raises the possibility that dysregulation of GSK3β and its inhibition by lithium may contribute to the disorder and its treatment, respectively. GSK3β has been linked to all of the primary abnormalities associated with Alzheimer's disease. These include interactions between GSK3β and components of the plaque-producing amyloid system, the participation of GSK3β in phosphorylating the microtubule-binding protein tau that may contribute to the formation of neurofibrillary tangles, and interactions of GSK3β with presenilin and other Alzheimer's disease-associated proteins. GSK3β also regulates cell survival, as it facilitates a variety of apoptotic mechanisms, and lithium provides protection from many insults. Thus, GSK3β has a central role regulating neuronal plasticity, gene expression, and cell survival, and may be a key component of certain psychiatric and neurodegenerative diseases.

Introduction

Glycogen synthase kinase-3β (GSK3β) was named for its ability to phosphorylate, and thereby inactivate, glycogen synthase, a key regulatory process in the synthesis of glycogen. With such an inauspicious beginning and moniker, it has come as some surprise to find that GSK3β is a critical central figure in many cellular signaling pathways. Now it is known that GSK3β is an important component of signaling systems coupled to receptors for insulin, a variety of growth factors and neurotrophins, and other signaling molecules. However, GSK3β is not only a key component of these signaling systems, but GSK3β is also a critically important regulator of several transcription factors which, in turn, can impact the control of the expression of numerous genes. Furthermore, the control of GSK3β activity is an important component in the regulation of complex functions, encompassing a wide scope ranging from survival at the cellular level to mood and cognition at the organism level. These actions, along with further evidence, have implicated the involvement of dysregulated GSK3β activity in certain psychiatric diseases, such as bipolar mood disorder, and neurodegenerative diseases, such as Alzheimer's disease. Thus, in spite of its inauspicious name, GSK3β is a fascinating enzyme that plays crucial roles in many major signaling processes that are involved in key functions of the brain and are associated with dysfunction in some major diseases of the central nervous system. This review focuses on recent developments in the understanding of GSK3β with an emphasis on processes likely to be important to neuronal function.

Section snippets

GSK3β

There are two highly homologous forms of mammalian GSK3, GSK3α and GSK3β (Woodgett, 1990). GSK3β, the smaller of the two proteins, consists of 482 amino acids with a molecular weight of 46,712 daltons, and contains a central protein kinase catalytic domain (Woodgett, 1991). An elegant historical synopsis of the discovery, cloning, and characterization of GSK3β is found in a review by Plyte et al. (1992). These authors also reported that GSK3β is ubiquitous throughout the animal kingdom (Plyte

Regulation of GSK3β

GSK3β is subject to multiple regulatory mechanisms. Although phosphorylation of GSK3β is the most widely studied mechanism of regulation, protein complex formation, intracellular localization, and mood-stabilizing drugs also have important regulatory influences on GSK3β activity. Such complex regulatory mechanisms are necessary for an enzyme that modifies multiple and diverse substrates, including metabolic, signaling, and structural proteins and transcription factors, and influences

What does GSK3β regulate?

GSK3β phosphorylates a diverse group of substrates (Table 1), few of which have been studied in great enough detail to describe the sites phosphorylated and the ultimate effect on substrate function. The first identified substrate of GSK3β was its namesake, the metabolic enzyme glycogen synthase (Section 4.1). Probably the substrate of GSK3β that has been studied in most depth is the structural protein tau (Section 4.2), a microtubule associated protein that is directly involved in the

Mood disorders

The major impetus for the concept that GSK3β may be involved in psychiatric disorders, and especially in bipolar mood disorder, derives from the finding that lithium, the primary therapeutic agent for bipolar mood disorder, is a selective inhibitor of GSK3β (Klein and Melton, 1996, Stambolic et al., 1996), as discussed in Section 3.4. In addition to directly inhibiting GSK3β, lithium also activates PI3K, and this causes a corresponding increase in Ser-9 phosphorylation, which is associated with

Summary

GSK3β is a fascinating enzyme with an astoundingly diverse number of actions in intracellular signaling systems. We find especially intriguing the evidence indicating that GSK3β has the key role of a ‘gatekeeper’ over a broad array of transcription factors. As this article has noted, many of the transcription factors activated when GSK3β is inhibited contribute to cell proliferation and survival. Thus, GSK3β appears to be a gatekeeper, maintaining cells at a regulated rate of proliferation and

Acknowledgements

Research in the authors' laboratory was supported by grants from the National Institutes of Health (MH38752, NS37768) and by a grant from the Alzheimer's Association. We thank our many laboratory colleagues for their valuable discussions concerning the topics discussed in this paper.

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The multifaceted roles of glycogen synthase kinase 3β in cellular signaling

Abstract

Introduction

Section snippets

GSK3β

Regulation of GSK3β

What does GSK3β regulate?

Mood disorders

Summary

Acknowledgements

J. Biol. Chem.

FEBS Lett.

Cell

Mol. Brain Res.

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

Curr. Opin. Genet. Dev.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Chem. Biol.

J. Biol. Chem.

Dev. Brain Res.

Prog. Neurobiol.

Cell

Neuron

Neuron

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

Neuroscience

J. Biol. Chem.

Neuron

Arch. Biochem. Biophys.

J. Biol. Chem.

Neurosci. Lett.

Cell

Cell

J. Biol. Chem.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Mechanism of activation of protein kinase B by insulin and IGF-1

EMBO J.

Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation

Genes Dev.

Suppression of TNF-alpha-induced apoptosis by NFκB

Science

In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3β

J. Neurochem.

Effect of increased glycogen synthase kinase-3 activity upon the maturation of the amyloid precursor protein in transfected cells

Neuroreport

Synergistic effects of tetrahydroaminoacridine and lithium on cholinergic function after excitotoxic basal forebrain lesions in rat

Pharmacopsychiatry

Activation of cAMP and mitogen responsive genes relies on a common nuclear factor

Nature

IκB: a specific inhibitor of the NF-κB transcription factor

Science

A 65-kD subunit of active NF-κB is required for inhibition of NF-κB by IκB

Genes Dev.

Function and activation of NF-κB in the immune system

Annu. Rev. Immunol.

The NFκB and IκB proteins: new discoveries and insights

Annu. Rev. Immunol.

Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3

Science

An essential role for NFκB in preventing TNF-alpha-induced cell death

Science

IκB interacts with the nuclear localization sequences of the subunits of NF-κB: a mechanism for cytoplasmic retention

Genes Dev.