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Description

Glycogen synthase kinase-3 beta/alpha (UniProts: P49841 and P49840, also known as EC: 2.7.11.26 and 2.7.11.26, GSK-3 beta/alpha, Serine/threonine-protein kinase GSK3B/alpha) is encoded by the GSK3B/GSK3A gene (Gene ID: 2932/2931) in human. GSK-3 is a multifunctional serine/threonine kinase, is a key regulator of numerous signaling pathways during embryogenesis and in metabolic control. Two isoforms of GSK-3 are reported in mammals: a 51 kDa GSK-3 alpha and a 47 kDa GSK-3 beta. The GSK-3 alpha contains a glycine-rich extension at its N-terminal. GSK-3 is constitutively active in cells and is regulated through inhibition of its activity. GSK-3 shows a preference for target proteins that are pre-phosphorylated at a `priming residue located C-terminal to the site of GSK-3 phosphorylation. Priming phosphorylation, although not absolutely required, enhances the efficiency of phosphorylation of most GSK-3 substrates. Phosphorylation of a threonine residue in the activation loop (T-loop) is considered to be essential for its activity. The T-loop of GSK-3 alpha is phosphorylated at Tyr279 and GSK-3 beta at Tyr216, which play a role in forcing open the substrate-binding site of the enzyme. A primary mechanism of GSK3 activity regulation is phosphorylation of N-terminal serine residues (Serine 9 in GSK3 beta and serine 21 in GSK3 alpha). Phosphorylation of these sites is inhibitory to GSK3 kinase activity because the phosphorylated N-terminus acts as a competitive inhibitor for primed substrates. GSK-3 beta is constitutively active in resting cells and treatment of cells with an agent, such as insulin, causes GSK-3 inactivation through a PI 3-kinase (PI 3-K)-dependent mechanism.