Glycogensynthetase Kinase 3

Glycogen synthetase kinase 3 (GSK3) is a substrate of AKT of serine-threonine kinase Ak. GSK3 is considered a key enzyme in glycogen metabolism and plays a crucial role in cell cycle regulation and proliferation.

Two isoforms of the enzyme (GSK3α and GSK3β) are known, with GSK3β frequently associated with tumors (de Groot RP et al. 1993; Buss H et al. 2004). In resting cells, the kinase is active and regulates the stability of numerous transcription factors. Its substrates include Activator protein 1 (AP-1), nuclear factor kappa B (NfκB), c-Myc, β-catenin, cAMP response element binding protein (C/EBP) and CAAT enhancer binding protein (CREB) (Ciani L et al. 2005; Gotschel Fet al. 2008). Often, their target proteins that promote cell survival are marked for protein degradation by phosphorylation and subsequently degraded via the proteasome.

Glycogen synthetase kinase 3β provides an interface between the PI3K/Akt and Wnt/β-catenin signaling pathways. Through Akt, the serine-threonine kinase GSK3β is phosphorylated and inactivated at the highly conserved N-terminal regulatory site on serine (amino acid 9). This results in β-catenin accumulating, migrating to the nucleus, and acting as a transcriptional activator with the transcription factors LEF/TCF. Dysregulation of GSK3β is frequently observed in pancreatic carcinoma, melanoma, colon carcinoma and hepatocellular carcinoma as well as in neurodegenerative diseases such as Alzheimer's disease (Ougolkov AV et al. 2006; Ma C et al. 2007).

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