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== Function == Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target.<ref name="pmid7803763">{{cite journal | vauthors = Woodgett JR | title = Regulation and functions of the glycogen synthase kinase-3 subfamily | journal = Seminars in Cancer Biology | volume = 5 | issue = 4 | pages = 269–275 | date = August 1994 | pmid = 7803763 }}</ref><ref name="pmid11579232">{{cite journal | vauthors = Woodgett JR | title = Judging a protein by more than its name: GSK-3 | journal = Science's STKE | volume = 2001 | issue = 100 | pages = re12 | date = September 2001 | pmid = 11579232 | doi = 10.1126/stke.2001.100.re12 | s2cid = 19052833 }}</ref><ref name="pmid11749387">{{cite journal | vauthors = Ali A, Hoeflich KP, Woodgett JR | title = Glycogen synthase kinase-3: properties, functions, and regulation | journal = Chemical Reviews | volume = 101 | issue = 8 | pages = 2527–2540 | date = August 2001 | pmid = 11749387 | doi = 10.1021/cr000110o | s2cid = 12925005 }}</ref> GSK-3 is active in a number of central intracellular signaling pathways, including cellular proliferation, migration, glucose regulation, and apoptosis. GSK-3 was originally discovered in the context of its involvement in regulating [[glycogen synthase]].<ref name="pmid6249596"/> After being primed by [[casein kinase 2]] (CK2), glycogen synthase gets phosphorylated at a cluster of three C-terminal serine residues, reducing its activity.<ref name="pmid19366350">{{cite journal | vauthors = Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A | title = Glycogen synthase kinase 3: more than a namesake | journal = British Journal of Pharmacology | volume = 156 | issue = 6 | pages = 885–898 | date = March 2009 | pmid = 19366350 | pmc = 2697722 | doi = 10.1111/j.1476-5381.2008.00085.x }}</ref> In addition to its role in regulating glycogen synthase, GSK-3 has been implicated in other aspects of glucose homeostasis, including the phosphorylation of insulin receptor [[IRS1]]<ref name="pmid15574412">{{cite journal | vauthors = Liberman Z, Eldar-Finkelman H | title = Serine 332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling | journal = The Journal of Biological Chemistry | volume = 280 | issue = 6 | pages = 4422–4428 | date = February 2005 | pmid = 15574412 | doi = 10.1074/jbc.M410610200 | doi-access = free }}</ref> and of the gluconeogenic enzymes [[phosphoenolpyruvate carboxykinase]] and [[glucose 6 phosphatase]].<ref name="pmid11334436">{{cite journal | vauthors = Lochhead PA, Coghlan M, Rice SQ, Sutherland C | title = Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression | journal = Diabetes | volume = 50 | issue = 5 | pages = 937–946 | date = May 2001 | pmid = 11334436 | doi = 10.2337/diabetes.50.5.937 | doi-access = free }}</ref> However, these interactions have not been confirmed, as these pathways can be inhibited without the up-regulation of GSK-3.<ref name="pmid19366350"/> GSK-3 has also been shown to regulate immune and migratory processes. GSK-3 participates in a number of signaling pathways in the innate immune response, including pro-inflammatory cytokine and interleukin production.<ref name="pmid16944320">{{cite journal | vauthors = Jope RS, Yuskaitis CJ, Beurel E | title = Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics | journal = Neurochemical Research | volume = 32 | issue = 4–5 | pages = 577–595 | date = Apr–May 2007 | pmid = 16944320 | pmc = 1970866 | doi = 10.1007/s11064-006-9128-5 }}</ref><ref name="pmid21095632">{{cite journal | vauthors = Wang H, Brown J, Martin M | title = Glycogen synthase kinase 3: a point of convergence for the host inflammatory response | journal = Cytokine | volume = 53 | issue = 2 | pages = 130–140 | date = February 2011 | pmid = 21095632 | pmc = 3021641 | doi = 10.1016/j.cyto.2010.10.009 }}</ref> The inactivation of [[GSK3B]] by various protein kinases also affects the adaptive immune response by inducing cytokine production and proliferation in naïve and memory CD4+ T cells.<ref name="pmid21095632"/> In cellular migration, an integral aspect of inflammatory responses, the inhibition of GSK-3 has been reported to play conflicting roles, as local inhibition at growth cones has been shown to promote motility while global inhibition of cellular GSK-3 has been shown to inhibit cell spreading and migration.<ref name="pmid16944320"/> GSK-3 is also integrally tied to pathways of cell proliferation and apoptosis. GSK-3 has been shown to phosphorylate [[Beta-catenin]], thus targeting it for degradation.<ref name="pmid22275880">{{cite journal | vauthors = Mills CN, Nowsheen S, Bonner JA, Yang ES | title = Emerging roles of glycogen synthase kinase 3 in the treatment of brain tumors | journal = Frontiers in Molecular Neuroscience | volume = 4 | pages = 47 | year = 2011 | pmid = 22275880 | pmc = 3223722 | doi = 10.3389/fnmol.2011.00047 | doi-access = free }}</ref> GSK-3 is therefore a part of the canonical [[Beta-catenin]]/[[Wnt signaling pathway|Wnt]] pathway, which signals the cell to divide and proliferate. GSK-3 phosphorylates cyclins D and E, which are important for the transition from G1 to S phase, and causes their degradation. The transcription factors c-myc and c-fos (also S phase promoters ), which are primarily phosphorylated by the dual-specificity tyrosine phosphorylation-regulated kinase, are also phosphorylated by GSK3, causing them to be degraded.<ref name="Glibo_2021">{{cite journal | vauthors = Glibo M, Serman A, Karin-Kujundzic V, Bekavac Vlatkovic I, Miskovic B, Vranic S, Serman L | title = The role of glycogen synthase kinase 3 (GSK3) in cancer with emphasis on ovarian cancer development and progression: A comprehensive review | journal = Bosnian Journal of Basic Medical Sciences | volume = 21 | issue = 1 | pages = 5–18 | date = February 2021 | pmid = 32767962 | pmc = 7861620 | doi = 10.17305/bjbms.2020.5036 }}</ref> GSK-3 also participates in a number of apoptotic signaling pathways by phosphorylating transcription factors that regulate [[apoptosis]].<ref name="pmid15102436"/> GSK-3 can promote apoptosis by both activating pro-apoptotic factors such as [[p53]]<ref name="pmid12048243">{{cite journal | vauthors = Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV, Jope RS | display-authors = 6 | title = Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 12 | pages = 7951–7955 | date = June 2002 | pmid = 12048243 | pmc = 123001 | doi = 10.1073/pnas.122062299 | doi-access = free | bibcode = 2002PNAS...99.7951W }}</ref> and inactivating survival-promoting factors through phosphorylation.<ref name="pmid11579131">{{cite journal | vauthors = Grimes CA, Jope RS | title = CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium | journal = Journal of Neurochemistry | volume = 78 | issue = 6 | pages = 1219–1232 | date = September 2001 | pmid = 11579131 | pmc = 1947002 | doi = 10.1046/j.1471-4159.2001.00495.x }}</ref> The role of GSK-3 in regulating apoptosis is controversial, however, as some studies have shown that GSK-3β knockout mice are overly sensitized to apoptosis and die in the embryonic stage, while others have shown that overexpression of GSK-3 can induce apoptosis.<ref name="pmid18701488">{{cite journal | vauthors = Kotliarova S, Pastorino S, Kovell LC, Kotliarov Y, Song H, Zhang W, Bailey R, Maric D, Zenklusen JC, Lee J, Fine HA | display-authors = 6 | title = Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation | journal = Cancer Research | volume = 68 | issue = 16 | pages = 6643–6651 | date = August 2008 | pmid = 18701488 | pmc = 2585745 | doi = 10.1158/0008-5472.CAN-08-0850 }}</ref> Overall, GSK-3 appears to both promote and inhibit apoptosis, and this regulation varies depending on the specific molecular and cellular context.<ref name="pmid22675363">{{cite journal | vauthors = Jacobs KM, Bhave SR, Ferraro DJ, Jaboin JJ, Hallahan DE, Thotala D | title = GSK-3β: A Bifunctional Role in Cell Death Pathways | journal = International Journal of Cell Biology | volume = 2012 | pages = 930710 | date = May 2012 | pmid = 22675363 | pmc = 3364548 | doi = 10.1155/2012/930710 | doi-access = free }}</ref> GSK-3 is also involved in nuclear transcriptional activator kappa B (NFκB) signaling pathway, Hedgehog signaling pathway, Notch signaling pathway, and epithelial-mesenchymal transition.<ref name="Glibo_2021" /> Due to its importance across numerous cellular functions, GSK-3 activity is subject to tight regulation and is considered an "Ace" among kinases.<ref>{{cite journal |last1=Mathuram |first1=TL |title=GSK-3: An "Ace" Among Kinases. |journal=Cancer Biotherapy & Radiopharmaceuticals |date=15 May 2024 |volume=39 |issue=9 |pages=619–631 |doi=10.1089/cbr.2024.0025 |pmid=38746994}}</ref> The speed and efficacy of GSK-3 phosphorylation is regulated by several factors. Phosphorylation of certain GSK-3 residues can increase or decrease its ability to bind substrate. Phosphorylation at tyrosine-216 in GSK-3β or tyrosine-279 in GSK-3α enhances the enzymatic activity of GSK-3, while phosphorylation of autoinhibitory serine-9 in GSK-3β or serine-21 in GSK-3α significantly decreases active site availability (see figure).<ref name="pmid16944320"/> Further, GSK-3 is unusual among kinases in that it usually requires a "priming kinase" to first phosphorylate a substrate. A phosphorylated serine or threonine residue located four amino acids C-terminal to the target site of phosphorylation allows the substrate to bind a pocket of positive charge formed by arginine and lysine residues.<ref name="pmid19366350"/><ref name="pmid12615961">{{cite journal | vauthors = Doble BW, Woodgett JR | title = GSK-3: tricks of the trade for a multi-tasking kinase | journal = Journal of Cell Science | volume = 116 | issue = Pt 7 | pages = 1175–1186 | date = April 2003 | pmid = 12615961 | pmc = 3006448 | doi = 10.1242/jcs.00384 }}</ref> Depending on the pathway in which it is being utilized, GSK-3 may be further regulated by cellular localization or the formation of protein complexes. The activity of GSK-3 is far greater in the nucleus and mitochondria than in the cytosol in cortical neurons,<ref name="pmid14663202">{{cite journal | vauthors = Bijur GN, Jope RS | title = Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria | journal = NeuroReport | volume = 14 | issue = 18 | pages = 2415–2419 | date = December 2003 | pmid = 14663202 | doi = 10.1097/00001756-200312190-00025 | s2cid = 43633965 }}</ref> while the phosphorylation of Beta-catenin by GSK-3 is mediated by the binding of both proteins to [[Axin]], a scaffold protein, allowing Beta-catenin to access the active site of GSK-3.<ref name="pmid16944320"/> Insulin indirectly inactivates GSK3 via downstream phosphorylation of the specific serine residues Ser21 and Ser9 in GSK-3 isoforms α and β, respectively, via the [[PI3K/Akt pathway]] (protein kinase B).<ref name="hermida-kumar-2017" /><ref name="insulin-akt-pp1-2019" />
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