NCBI Summary:
Glycogen synthase kinase-3 (GSK3) is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms, alpha (GSK3A; MIM 606784) and beta, show a high degree of amino acid homology (Stambolic and Woodgett, 1994 [PubMed 7980435]). GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation (Plyte et al., 1992 [PubMed 1333807]).[supplied by OMIM]
General function
Enzyme
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Cellular localization
Cytoplasmic
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Ovarian function
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Expression regulated by
Growth Factors/ cytokines
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Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development. Liu L et al. Communication between mammalian oocytes and their surrounding granulosa cells through the Kit-Kit ligand (KL, or stem cell factor, SCF) system has been shown to be crucial for follicular development. Our previous studies (Reddy et al. 2005, Liu et al. 2006) have indicated that the intra-oocyte KL-Kit-PI3 kinase (PI3K)-Akt-Foxo3a cascade may play an important role in follicular activation and early development. In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes. Also, treatment of cultured mouse oocytes with soluble KL not only leads to increased Akt kinase activity in the oocytes, which can phosphorylate recombinant GSK-3 in vitro, but also leads to phosphorylation of oocyte GSK-3alpha and GSK-3beta, which can result in the inactivation of GSK-3 function in oocytes. In addition, we have shown that the regulation of GSK-3alpha and GSK-3beta in cultured oocytes by soluble KL is accomplished through PI3K, since the PI3K-specific inhibitor LY294002 completely abolished the KL-induced phosphorylation of GSK-3alpha and GSK-3beta. Moreover, blockage of the Kit signaling pathway by a Kit function-blocking antibody, ACK2, resulted in reduced phosphorylation of GSK-3. Taken together, our data suggest that the cascade from granulosa cell-derived KL to Kit-PI3K-Akt-GSK-3 in oocytes may take part in regulation of oocyte growth and early ovarian follicular development.
Ovarian localization
Oocyte
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Expression analysis of glycogen synthase kinase-3 in human tissues.
Lau KF,et al
Human glycogen synthase kinase-3 (GSK-3) is a multisubstrate, proline-directed kinase that phosphorylates tau, beta-amyloid and neurofilaments. In this study, the expression levels of the two GSK-3 isoforms, alpha and beta, RNA and proteins in different human tissues were examined. Northern analysis demonstrated that GSK-3alpha is encoded by a 2.6-kb mRNA and GSK-3beta by 8.3- and 2.8-kb mRNAs. The two GSK-3beta mRNA species were variably expressed in different tissues. Northern and quantitative polymerase chain reaction demonstrated that both GSK-3alpha and GSK-3beta mRNA were prominently expressed in testis, thymus, prostate and ovary but were low in adult lung and kidney. Western blot analysis showed that the 51-kDa GSK-3alpha protein was highly expressed in lung, ovary, kidney and testis, whereas the 46-kDa GSK-3beta protein was highly expressed in lung, kidney and brain. The differential expression of GSK-3alpha and GSK-3beta mRNA and proteins and the lack of relationship between transcription and translation in some tissues indicate that GSK-3alpha and GSK-3beta are subject to different means of regulation.
Follicle stages
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Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Loss of Glycogen Synthase Kinase 3 Isoforms During Murine Oocyte Growth Induces Offspring Cardiac Dysfunction. Monteiro da Rocha A et al. (2015) Glycogen synthase kinase-3 (GSK3) is a constitutively active serine threonine kinase with i) two isoforms (GSK3A and GSK3B) having unique and overlapping functions, ii) multiple molecular intracellular mechanisms involving phosphorylation of diverse substrates, and iii) implications in pathogenesis of many diseases. Insulin causes phosphorylation and inactivation of GSK3 and mammalian oocytes have a functional insulin signaling pathway whereby prolonged elevated insulin during follicle/oocyte development causes GSK3 hyperphosphorylation, reduced GSK3 activity, and altered oocyte chromatin remodeling. Periconceptional diabetes and chronic hyperinsulinemia are associated with congenital malformations and onset of adult diseases of cardiovascular origin. Objectives were to produce transgenic mice with individual or concomitant loss of GSK3A and/or GSK3B and investigate the in vivo role of oocyte GSK3 on fertility, fetal development, and offspring health. Wild type males bred to females with individual or concomitant loss of oocyte GSK3 isoforms did not have reduced fertility. However, concomitant loss of GSK3A and GSK3B in the oocyte significantly increased neonatal death rate due to congestive heart failure secondary to ventricular hyperplasia. Individual loss of oocyte GSK3A or GSK3B did not induce this lethal phenotype. In conclusion, absence of oocyte GSK3 in the periconceptional period does not alter fertility yet causes offspring cardiac hyperplasia, cardiovascular defects, and significant neonatal death. These results support a developmental mechanism by which periconceptional hyperinsulinemia associated with maternal metabolic syndrome, obesity, and/or diabetes can act on the oocyte and impact offspring cardiovascular development, function, and congenital heart malformation.//////////////////