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