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