Hindawi Publishing Corporation International Journal of Cell Biology Volume 2012, Article ID 930710, 11 pages doi:10.1155/2012/930710 Review Article GSK-3β: A Bifunctional Role in Cell Death Pathways Keith M. Jacobs,1 Sandeep R. Bhave,2 Daniel J. Ferraro,1 Jerry J. Jaboin,1, 3 Dennis E. Hallahan,1, 3, 4 and Dinesh Thotala1, 3 1 Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO 63108, USA 2 School of Medcine, Washington University in St. Louis, St. Louis, MO 63108, USA 3 Siteman Cancer Center, St. Louis, MO 63110, USA 4 Mallinckrodt Institute of Radiology, St. Louis, MO 63110, USA Correspondence should be addressed to Dinesh Thotala, dthotala@radonc.wustl.edu Received 6 January 2012; Revised 9 March 2012; Accepted 12 March 2012 Academic Editor: Paolo Pinton Copyright © 2012 Keith M. Jacobs et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Although glycogen synthase kinase-3 beta (GSK-3β) was originally named for its ability to phosphorylate glycogen synthase and regulate glucose metabolism, this multifunctional kinase is presently known to be a key regulator of a wide range of cellular functions. GSK-3β is involved in modulating a variety of functions including cell signaling, growth metabolism, and various transcription factors that determine the survival or death of the organism. Secondary to the role of GSK-3β in various diseases including Alzheimer’s disease, inﬂammation, diabetes, and cancer, small molecule inhibitors of GSK-3β are gaining signiﬁcant attention. This paper is primarily focused on addressing the bifunctional or conﬂicting roles of GSK-3β in both the promotion of cell survival and of apoptosis. GSK-3β has emerged as an important molecular target for drug development. 1. Introduction Glycogen synthase kinase-3 is a ubiquitously expressed protein kinase that exists in two isoforms, α and β. Originally identiﬁed based on its role in glycogen biosynthesis based on its inactivating phosphorylation of glycogen synthase, it has since been found to regulate a myriad of functions through Wnt and other signaling pathways [1]. The two isoforms are strongly conserved within their kinase domain but diﬀer greatly at the C-terminus, while the α isoform additionally contains a glycine-rich N-terminus extension [2]. Our paper will focus on the β isoform due to its more established role in cell survival and viability. Glycogen synthase kinase- 3 beta (GSK-3β) is involved in the regulation of a wide range of cellular functions including diﬀerentiation, growth, proliferation motility, cell cycle progression, embryonic development, apoptosis, and insulin response [1–8]. It has emerged as an important regulator of neuronal, endothelial, hepatocyte, ﬁbroblast, and astrocyte cell death in response to various stimuli [6, 7, 9]. GSK-3β is comprised of 12 exons in humans and 11 exons in mice with the ATG start codon located within exon 1 and the TAG stop codon found in the terminal exon. The gene product is a 46 kDa protein consisting of 433 amino acids in the human and 420 amino acids in the mouse. Figure 1 shows the overall structure of GSK-3β. It is similar to other Ser/Thr kinases [10, 11]. The N-terminal domain is comprised of the ﬁrst 135 residues and forms a 7-strand β-barrel motif. A small linker region connects the N-terminal domain to the central α-helical domain formed by residues 139 through 342. The ATP-binding site lies at the interface of the N-terminal and α-helical domains. Residues 343 through 433 form the C-terminal domain, which is outside of the classical Ser/Thr kinase core fold. These residues form a helix/loop domain that interacts with the core α-helical domain. The N-terminal amino acids 78 through 92 are necessary for association with p53 (Figure 1). The activity of GSK-3β can be reduced by phosphorylation at Ser-9. Several kinases are able to mediate this modiﬁcation, including p70S6 kinase, p90RSK, PKC, and Akt [12, 13]. In opposition to the inhibitory phosphorylation of GSK-3β at Ser-9, phosphorylation of GSK-3β at Tyr-216 by ZAK1 or Fyn increases its enzyme activity [14] (Figure 2).