GSK3 Signaling Pathway

1. GSK3 Signaling Pathway Glycogen synthase kinase 3s are serine/threonine kinases which were originally found as key regulatory enzymes in glucose metabolism. Mammals express two GSK3 isoforms, one is GSK3α (51kDa) and the other is GSK3β (47kDa). They are encoded by different genes, which are about 85% homologous to each other, with 95% identity in the kinase domains. There are two key functional domains of GSK3, a primed-substrate binding domain that recruits substrates to GSK3, and a kinase domain that phosphorylates the substrates. The former domain provides a binding site for major GSK3 substrates (Figure 2A, based on PDB ID: 4nm), those primed by prephosphorylation. The most common target for phosphorylation by GSK3 is the pre-phosphorylated sequence, S/T-X-X-X-S/T(P), where GSK3 phosphorylates a serine/threonine four residues N-terminal to a pre-phosphorylated serine/threonine. GSK3 has an unconventional character of a constitutively active kinase, the substrate of which typically needs to be pre-phosphorylated by another kinase, and it is inhibited rather than activated. It is one of the few signaling mediators that play important roles in a variety of signaling pathways, including those activated by Wnts, hedgehog and G protein-coupled ligands. The answer to GSK3’s actions may be the multiple regulatory mechanisms available to arrange its substrate-specific actions. We categorized these crucial mechanisms to include the regulatory phosphorylation of GSK3 itself, the regulation of substrate availability, the subcellular localization of GSK3 and its substrates, and the incorporation of GSK3 into protein complexes. GSK3 involves in almost every aspect of cellular signaling and is involved in an unparalleled number of disease processes. https://www.creative-diagnostics.com/gsk3-signaling-pathway.htm