%0 Journal Article
%T GSK-3 : A Bifunctional Role in Cell Death Pathways
%A Keith M. Jacobs
%A Sandeep R. Bhave
%A Daniel J. Ferraro
%A Jerry J. Jaboin
%A Dennis E. Hallahan
%A Dinesh Thotala
%J International Journal of Cell Biology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/930710
%X Although glycogen synthase kinase-3 beta (GSK-3¦Â) 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-3¦Â 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-3¦Â in various diseases including Alzheimer¡¯s disease, inflammation, diabetes, and cancer, small molecule inhibitors of GSK-3¦Â are gaining significant attention. This paper is primarily focused on addressing the bifunctional or conflicting roles of GSK-3¦Â in both the promotion of cell survival and of apoptosis. GSK-3¦Â 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, ¦Á and ¦Â. 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 ¦Á isoform additionally contains a glycine-rich N-terminus extension [2]. Our paper will focus on the ¦Â isoform due to its more established role in cell survival and viability. Glycogen synthase kinase-3 beta (GSK-3¦Â) 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¨C8]. 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-3¦Â 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-3¦Â. 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 ¦Â-barrel motif. A small linker region connects the N-terminal domain to the central ¦Á-helical domain formed by residues 139 through 342. The ATP-binding site lies at the interface of the N-terminal and ¦Á-helical
%U http://www.hindawi.com/journals/ijcb/2012/930710/