InterPro domain: IPR039192

Glycogen synthase kinase 3 (GSK3) is a mutifunctional kinase involved in many cellular processes including cell division, proliferation, differentiation, adhesion, and apoptosis. In plants, GSK3 plays a role in the response to osmotic stress [ 1 , 2 ]. In Caenorhabditis elegans, it plays a role in regulating normal oocyte-to-embryo transition and response to oxidative stress [ 3 ]. In Chlamydomonas reinhardtii, GSK3 regulates flagellar length and assembly [ 4 ].

Mammals have two isoforms of GSK3, GSK3alpha and GSK3beta, which show both distinct and redundant functions. The two isoforms differ mainly in their N-termini [ 5 ]. They are both involved in axon formation and in Wnt signaling [ 6 , 7 ]. They play distinct roles in cardiogenesis, with GSKalpha being essential in cardiomyocyte survival, and GSKbeta regulating heart positioning and left-right symmetry [ 8 ]. GSK3beta was first identified as a regulator of glycogen synthesis, but has since been determined to play other roles. It regulates the degradation of beta-catenin and IkB. Beta-catenin is the main effector of Wnt, which is involved in normal haematopoiesis and stem cell function. IkB is a central inhibitor of NF-kB, which is critical in maintaining leukemic cell growth. GSK3beta is enriched in the brain and is involved in regulating neuronal signaling pathways. It is implicated in the pathogenesis of many diseases including Type II diabetes, obesity, mood disorders, Alzheimer's disease, osteoporosis, and some types of cancer, among others [ 9 , 10 , 11 ].

1. An Arabidopsis GSK3/shaggy-like gene that complements yeast salt stress-sensitive mutants is induced by NaCl and abscisic acid. Plant Physiol. 119, 1527-34
2. Organization and expression of the GSK3/shaggy kinase gene family in the moss Physcomitrella patens suggest early gene multiplication in land plants and an ancestral response to osmotic stress. J. Mol. Evol. 61, 99-113
3. Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3. Proc. Natl. Acad. Sci. U.S.A. 102, 16275-80
4. Regulation of flagellar assembly by glycogen synthase kinase 3 in Chlamydomonas reinhardtii. Eukaryotic Cell 3, 1307-19
5. N-terminal cleavage of GSK-3 by calpain: a new form of GSK-3 regulation. J. Biol. Chem. 282, 22406-13
6. GSK3 signalling in neural development. Nat. Rev. Neurosci. 11, 539-51
7. Judging a protein by more than its name: GSK-3. Sci. STKE 2001, re12
8. Glycogen synthase kinase 3 alpha and 3 beta have distinct functions during cardiogenesis of zebrafish embryo. BMC Dev. Biol. 7, 93
9. The role of glycogen synthase kinase 3 in the early stages of Alzheimers' disease. FEBS Lett. 582, 3848-54
10. Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: the role of GSK-3beta in the maintenance of steady-state levels of insulin receptor signaling molecules and Na(v)1.7 sodium channel in adrenal chromaffin cells. J. Pharmacol. Sci. 109, 157-61
11. GSK3beta: role in therapeutic landscape and development of modulators. Br. J. Pharmacol. 160, 1-19