Multifunctional enzyme glycogen synthase kinase 3

Isolated more than 25 years ago, the multifunctional enzyme, glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase present in all eukaryotes. It was isolated as a protein kinase that phosphorylated and inactivated glycogen synthase (Embi et al., 1980) and is the final and rate-limiting enzyme in glycogen biosynthesis. Accumulating data showed its involvement in a variety of signaling pathways that control cellular motility, protein translation, cell proliferation, growth, differentiation and apoptosis (Cohen and Frame, 2001; Frame and Cohen, 2001; Jope and Johnson, 2004). Mechanisms that regulate the functions of GSK-3 include phosphorylation, protein complex formation and subcellular distribution. Therefore, the dysregulation of GSK-3 is obviously linked to several pathological conditions, such as diabetes, neuronal abnormalities, Alzheimer’s disease (Bhat et al., 2004; Hernandez et al., 2004; Fulga et al., 2007; Cohen and Goedart, 2004), schizophrenia (Emamian et al., 2004), dopamine-associated behaviors (Beaulieu et al., 2004), bipolar disorders (Klein and Melton, 1996), Parkinson’s disease (Kozikowski et al., 2006) and cancer. Taken together, the important cellular role of GSK-3 has prompted immense efforts towards understanding the regulatory role of the molecule and its functioning. And, methods that are capable of alleviating the harmful impact of GSK-3 in pathological conditions are being devised. Plant genomes also harbour GSKs and are encoded by a multigene family (Bianchi et al., 1994; Decroocq-Ferrant et al., 1995; Dornelas et al., 1998; 1999; 2000; Einzenberger et al., 1995; Jonak et al., 1995; 2000; Tichtinsky et al., 1998). Arabidopsis has ten different GSKs. Genetic and biochemical approaches indicate that different plant GSKs are also involved in diverse processes including hormonal signal transduction, development and biotic/abiotic stress responses.
In Caenorhabditis elegans, GSK3 is involved in the endoderm–mesoderm cell-fate decision (Kim and Kimmel, 2000; Thorpe et al., 2000). While in Dictyostelium, GSK-3 is required for proper cell-fate specification between stalk and spore cells (Kim and Kimmel, 2000; Harwood, 2000). The yeast Saccharomyces cerevisiae has four genes encoding the GSKs, viz. MDS1 (RIM11, ScGSK-3), MCK1, MRK1 and YOL128c. The functions of MRK1 and YOL128c are unknown. Mammals generally express two homologues of GSK-3, GSK-3α and GSK-3β, which are encoded by separate genes. The two GSK-3 isoforms are strongly conserved within their kinase domains, but differ substantially at their amino and carboxyl termini. Due to its well-established role in cell survival and viability, and very little information about the interplay between GSK-3 beta regulation and cell death stimuli in promoting apoptosis and necrosis, the current study focusses on the β isoform. (still 5% material copied!)

Of these two isoforms, Glycogen synthase kinase-3 beta (GSK-3β) regulates a wide range of cellular functions such as growth, differentiation, proliferation, motility, cell cycle progression, embryonic development, apoptosis and insulin response (Frame and Cohen, 2001; Doble and Woodgett, 2003; Jope and Johnson, 2004; Grimes and Jope, 2001; Luo 2009; Pap and Cooper 2002; Sanchez et al., 2003; Yazlovitskaya et al., 2006; Doble et al., 2011). Aberrant GSK-3β expression leads to many pathological conditions. It’s dual role as a tumor suppressor and tumor promoter in cancer is very intriguing and was believed to be dependent on both the cell type and its signaling environment. For example, GSK-3β manifests its role as a tumor suppressor by inhibiting androgen receptor-stimulated cell growth in prostate cancer (Wang et al., 2004). On the other hand, its abundant expression in colorectal cancer (Shakoori et al., 2005; 2007) and participation in nuclear factor-κB (NF-κB)-mediated cell survival in pancreatic cancer (Ougolkov et al., 2005) makes it a tumor promoter candidate. In response to various stimuli, cells of the nervous system and liver, those that line the blood vessels (endothelium), fibroblast and astrocytes use GSK-3β as an important regulator of cell death (Pap and Cooper, 2002; Sanchez et al., 2003; Yazlovitskaya et al., 2006). Further, its dual functions in the regulation of cell survival, either as an activator or inhibitor of apoptosis has been documented (Jope and Johnson, 2004; Beurel and Jope, 2006).our essay in here…

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