GSK-3: Difference between revisions

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{{mergefrom|Gsk 3 inhibitor|date=December 2018}}
{{infobox protein
{{infobox protein
|Name= [[GSK3A|glycogen synthase kinase 3 alpha]]
|Name= [[GSK3A|glycogen synthase kinase 3 alpha]]
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|Name=[[GSK3B|glycogen synthase kinase 3 beta]]
|Name=[[GSK3B|glycogen synthase kinase 3 beta]]
|image= 1J1B.png
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|caption=[[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of human GSK-3β (rainbow colored, [[N-terminus]] = blue, [[C-terminus]] = red) bound to phosphoaminophosphonic acid-adenylate ester (spheres).<ref name="pmid14993667">{{PDB|1J1B}}; {{cite journal |vauthors=Aoki M, Yokota T, Sugiura I, Sasaki C, Hasegawa T, Okumura C, Ishiguro K, Kohno T, Sugio S, Matsuzaki T | title = Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta | journal = Acta Crystallogr. D | volume = 60 | issue = Pt 3 | pages = 439–46 |date=March 2004 | pmid = 14993667 | doi = 10.1107/S090744490302938X | url = }}</ref>
|caption=[[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of human GSK-3β (rainbow colored, [[N-terminus]] = blue, [[C-terminus]] = red) bound to phosphoaminophosphonic acid-adenylate ester (spheres).<ref name="pmid14993667">{{PDB|1J1B}}; {{cite journal | vauthors = Aoki M, Yokota T, Sugiura I, Sasaki C, Hasegawa T, Okumura C, Ishiguro K, Kohno T, Sugio S, Matsuzaki T | title = Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta | journal = Acta Crystallographica Section D| volume = 60 | issue = Pt 3 | pages = 439–46 | date = March 2004 | pmid = 14993667 | doi = 10.1107/S090744490302938X }}</ref>
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|HGNCid=4617
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'''Glycogen synthase kinase 3''' is a [[serine/threonine protein kinase]] that mediates the addition of phosphate molecules onto [[serine]] and [[threonine]] amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, [[Glycogen synthase]],<ref name="pmid6249596">{{cite journal |vauthors=Embi N, Rylatt DB, Cohen P | title = Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase | journal = Eur J Biochem | volume = 107 | issue = 2 | pages = 519–27 |date=June 1980 | pmid = 6249596 | doi = 10.1111/j.1432-1033.1980.tb06059.x| url =  }}</ref> GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways.<ref name="pmid15102436">{{cite journal |vauthors=Jope RS, Johnson GV | title = The glamour and gloom of glycogen synthase kinase-3 | journal = Trends Biochem Sci | volume = 29 | issue = 2 | pages = 95–102 |date=Feb 2004 | pmid = 15102436 | doi = 10.1016/j.tibs.2003.12.004| url =  }}</ref> In mammals GSK-3 is encoded by two known genes, GSK-3 alpha ([[GSK3A]]) and GSK-3 beta ([[GSK3B]]).
'''Glycogen synthase kinase 3''' is a [[serine/threonine protein kinase]] that mediates the addition of phosphate molecules onto [[serine]] and [[threonine]] amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, [[Glycogen synthase]],<ref name="pmid6249596">{{cite journal | vauthors = Embi N, Rylatt DB, Cohen P | title = Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase | journal = European Journal of Biochemistry | volume = 107 | issue = 2 | pages = 519–27 | date = June 1980 | pmid = 6249596 | doi = 10.1111/j.1432-1033.1980.tb06059.x }}</ref> GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways.<ref name="pmid15102436">{{cite journal | vauthors = Jope RS, Johnson GV | title = The glamour and gloom of glycogen synthase kinase-3 | journal = Trends in Biochemical Sciences | volume = 29 | issue = 2 | pages = 95–102 | date = February 2004 | pmid = 15102436 | doi = 10.1016/j.tibs.2003.12.004 }}</ref> In mammals GSK-3 is encoded by two known genes, GSK-3 alpha ([[GSK3A]]) and GSK-3 beta ([[GSK3B]]).
GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes ([[Diabetes mellitus type 2]]), [[Alzheimer's Disease]], [[inflammation]], [[cancer]], and [[bipolar disorder]].
GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes ([[Diabetes mellitus type 2]]), [[Alzheimer's Disease]], [[inflammation]], [[cancer]], and [[bipolar disorder]].


==Mechanism==
==Mechanism==


[[File:GSK3 active site.png|thumb|left|alt=Active site of GSK-3|The active site of GSK-3. The three residues in blue bind the priming phosphate on the substrate, as demonstrated by the ligand. Residues D181, D200, K85, and E97.]]GSK-3 functions by [[phosphorylation|phosphorylating]] a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a "priming" phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, binds the terminal phosphate of ATP and transfers it to the target location on the substrate (see figure 1).<ref name="pmid11440715">{{cite journal |vauthors=Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH | title = Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. | journal = Cell | volume = 105 | issue = 6 | pages = 721–32 |date=June 2001 | pmid = 11440715 | doi = 10.1016/S0092-8674(01)00374-9| url =  }}</ref>
[[File:GSK3 active site.png|thumb|left|alt=Active site of GSK-3|The active site of GSK-3. The three residues in blue bind the priming phosphate on the substrate, as demonstrated by the ligand. Residues D181, D200, K85, and E97.]]GSK-3 functions by [[phosphorylation|phosphorylating]] a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a "priming" phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, binds the terminal phosphate of ATP and transfers it to the target location on the substrate (see figure 1).<ref name="pmid11440715">{{cite journal | vauthors = Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH | title = Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition | journal = Cell | volume = 105 | issue = 6 | pages = 721–32 | date = June 2001 | pmid = 11440715 | doi = 10.1016/S0092-8674(01)00374-9 }}</ref>


==Function==
== Function ==


Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target.<ref name="pmid7803763">{{cite journal | author = Woodgett JR | title = Regulation and functions of the glycogen synthase kinase-3 subfamily | journal = Semin. Cancer Biol. | volume = 5 | issue = 4 | pages = 269–75 |date=August 1994 | pmid = 7803763 | doi = | url =  }}</ref><ref name="pmid11579232">{{cite journal | author = Woodgett JR | title = Judging a protein by more than its name: GSK-3 | journal = Sci. STKE | volume = 2001 | issue = 100 | pages = RE12 |date=September 2001 | pmid = 11579232 | doi = 10.1126/stke.2001.100.re12 | url =  }}</ref><ref name="pmid11749387">{{cite journal |vauthors=Ali A, Hoeflich KP, Woodgett JR | title = Glycogen synthase kinase-3: properties, functions, and regulation | journal = Chem. Rev. | volume = 101 | issue = 8 | pages = 2527–40 |date=August 2001 | pmid = 11749387| doi = 10.1021/cr000110o }}</ref>  GSK-3 is active in a number of central intracellular signaling pathways, including cellular proliferation, migration, glucose regulation, and apoptosis.
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 = 269–75 | date = August 1994 | pmid = 7803763 | doi =  }}</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 }}</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 = 2527–40 | date = August 2001 | pmid = 11749387 | doi = 10.1021/cr000110o }}</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 = Br J Pharmacol | volume = 156 | issue = 6 | pages = 885–98 |date=Mar 2009 | pmid = 19366350 | doi = 10.1111/j.1476-5381.2008.00085.x| url = | pmc=2697722}}</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 = J Biol Chem | volume = 280 | issue = 6 | pages = 4422–8 |date=Feb 2005 | pmid = 15574412 | doi = 10.1074/jbc.M410610200| url =  }}</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 = 937–46 |date=May 2001 | pmid = 11334436 | doi = 10.2337/diabetes.50.5.937| url =  }}</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 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 = 885–98 | 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 = 4422–8 | date = February 2005 | pmid = 15574412 | doi = 10.1074/jbc.M410610200 }}</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 = 937–46 | date = May 2001 | pmid = 11334436 | doi = 10.2337/diabetes.50.5.937 }}</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 = Neurochem Res | volume = 32 | issue = 4–5 | pages = 577–95 |date=Apr–May 2007 | pmid = 16944320 | doi = 10.1007/s11064-006-9128-5| url = | pmc=1970866}}</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 = 130–40 |date=Feb 2011 | pmid = 21095632 | doi = 10.1016/j.cyto.2010.10.009| url = | pmc=3021641}}</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 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 = 577–95 | 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 = 130–40 | 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 = Front Mol Neurosci | volume = 4 | year = 2011 | pmid = 22275880 | doi = 10.3389/fnmol.2011.00047| url = | pmc=3223722 | pages=47}}</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 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 | title = Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage. | journal = Proc Natl Acad Sci U S A | volume = 99 | issue = 12 | pages = 7951–5 |date=Jun 2002 | pmid = 12048243 | doi = 10.1073/pnas.122062299| url = | pmc=123001}}</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 = J Neurochem | volume = 78 | issue = 6 | pages = 1219–32 |date=Sep 2001 | pmid = 11579131 | doi = 10.1046/j.1471-4159.2001.00495.x| url = | pmc=1947002}}</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 | title = Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation. | journal = Cancer Res | volume = 68 | issue = 16 | pages = 6643–51 |date=Aug 2008 | pmid = 18701488 | doi = 10.1158/0008-5472.CAN-08-0850| url = | pmc=2585745}}</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 = Int J Cell Bio | volume = 2012 | pages = 930710 |date=May 2012 | pmid = 22675363 | doi = 10.1155/2012/930710| url = | pmc=3364548}}</ref>
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 }}</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 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 | 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 = 7951–5 | date = June 2002 | pmid = 12048243 | pmc = 123001 | doi = 10.1073/pnas.122062299 }}</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 = 1219–32 | 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 | 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 = 6643–51 | 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 }}</ref>


==Regulation==
==Regulation==
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Due to its importance across numerous cellular functions, GSK-3 activity is subject to tight regulation.
Due to its importance across numerous cellular functions, GSK-3 activity is subject to tight regulation.


The speed and efficacy of GSK-3 phosphorylation is regulated by a number of 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 serine-9 in GSK-3β or serine-21 in GSK-3α significantly decreases active site availability (see Figure 1).<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 = J Cell Sci | volume = 116 | issue = 7 | pages = 1175–86 |date=Apr 2003 | pmid = 12615961 | doi = 10.1242/jcs.00384| url = | pmc=3006448}}</ref>
The speed and efficacy of GSK-3 phosphorylation is regulated by a number of 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 serine-9 in GSK-3β or serine-21 in GSK-3α significantly decreases active site availability (see Figure 1).<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 = 1175–86 | 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 = 2415–9|date=Dec 2003 | pmid = 14663202 | doi = 10.1097/01.wnr.0000099609.19426.70| url =  }}</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"/>
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 = 2415–9 | date = December 2003 | pmid = 14663202 | doi = 10.1097/00001756-200312190-00025 }}</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"/>


==Disease relevance==
==Disease relevance==


Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in [[Alzheimer's disease]], [[type 2 diabetes mellitus]] (T2DM), some forms of [[cancer]], and [[bipolar disorder]].
Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in [[Alzheimer's disease]], [[type 2 diabetes mellitus]] (T2DM), some forms of [[cancer]], and [[bipolar disorder]].<ref name="Saraswati_2017">{{cite journal | vauthors = Saraswati AP, Ali Hussaini SM, Krishna NH, Babu BN, Kamal A | title = Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions | journal = European Journal of Medicinal Chemistry | volume = 144 | issue =  | pages = 843–858 | date = January 2018 | pmid = 29306837 | doi = 10.1016/j.ejmech.2017.11.103 }}</ref>


It has now been shown that [[Lithium (medication)|lithium]], which is used as a treatment for [[bipolar disorder]], acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition stabilizes mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect.<ref name="pmid16944320"/> Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock.<ref name="pmid16944320"/> Elements of the circadian clock may be connected with predisposition to bipolar mood disorder.<ref>"pbmid24679394"</ref>
It has now been shown that [[Lithium (medication)|lithium]], which is used as a treatment for [[bipolar disorder]], acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition stabilizes mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect.<ref name="pmid16944320"/> Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock.<ref>{{cite journal | vauthors = Yin L, Wang J, Klein PS, Lazar MA | title = Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock | journal = Science | volume = 311 | issue = 5763 | pages = 1002–5 | date = February 2006 | pmid = 16484495 | doi = 10.1126/science.1121613 }}</ref> Elements of the circadian clock may be connected with predisposition to bipolar mood disorder.<ref>{{cite journal | vauthors = Rybakowski JK, Dmitrzak-Weglarz M, Dembinska-Krajewska D, Hauser J, Akiskal KK, Akiskal HH | title = Polymorphism of circadian clock genes and temperamental dimensions of the TEMPS-A in bipolar disorder | journal = Journal of Affective Disorders | volume = 159 | pages = 80–4 | date = April 2014 | pmid = 24679394 | doi = 10.1016/j.jad.2014.02.024 | url = http://europepmc.org/abstract/med/24679394 }}</ref>


GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of [[Beta amyloid|amyloid-β]] (Aβ) deposits and the formation of [[neurofibrillary tangle]]s. GSK-3 is thought to directly promote Aβ production and to be tied to the process of the [[hyperphosphorylation]] of [[tau protein]]s, which leads to the tangles.<ref name="pmid15102436"/><ref name="pmid16944320"/> Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing.<ref name="pmid19038340">{{cite journal |vauthors=Hu S, Begum AN, Jones MR, Oh MS, Beech WK, Beech BH, Yang F, Chen P, Ubeda OJ, Kim PC, Davies P, Ma Q, Cole GM, Frautschy SA | title = GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals. | journal = Neurobiol Dis. | volume = 33 | issue = 2 | pages = 193–206 |date=Feb 2009 | pmid = 19038340 | doi = 10.1016/j.nbd.2008.10.007| url = }}</ref>
GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of [[Beta amyloid|amyloid-β]] (Aβ) deposits and the formation of [[neurofibrillary tangle]]s. GSK-3 is thought to directly promote Aβ production and to be tied to the process of the [[hyperphosphorylation]] of [[tau protein]]s, which leads to the tangles.<ref name="pmid15102436"/><ref name="pmid16944320"/> Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing.<ref name="pmid19038340">{{cite journal | vauthors = Hu S, Begum AN, Jones MR, Oh MS, Beech WK, Beech BH, Yang F, Chen P, Ubeda OJ, Kim PC, Davies P, Ma Q, Cole GM, Frautschy SA | title = GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals | journal = Neurobiology of Disease | volume = 33 | issue = 2 | pages = 193–206 | date = February 2009 | pmid = 19038340 | doi = 10.1016/j.nbd.2008.10.007 | pmc = 4313761 }}</ref>


In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote [[apoptosis]] in some cases, it has also been reported to be a key factor in [[tumorigenesis]] in some cancers.<ref name="Wang2008">{{cite journal | author = Wang Z | title = Leukaemia: GSK-3 as a cancer promoter | journal = Nature | volume = 455 | pages = 1205–10 |date=Oct 2008 | doi = 10.1038/nature07284 | url = }}</ref> Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.<ref name="pmid18701488"/><ref name="pmid22201186">{{cite journal |vauthors=Marchand B, Tremblay I, Cagnol S, Boucher MJ | title = Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms. | journal = Carcinogenesis | volume = 33| issue = 3| pages = 529–37|date=Jan 2012 | pmid = 22201186 | doi = 10.1093/carcin/bgr309| url =  }}</ref>
In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote [[apoptosis]] in some cases, it has also been reported to be a key factor in [[tumorigenesis]] in some cancers.<ref name="Wang2008">{{cite journal | vauthors = Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML | title = Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy | journal = Nature | volume = 455 | issue = 7217 | pages = 1205–9 | date = October 2008 | pmid = 18806775 | doi = 10.1038/nature07284 | pmc = 4084721 }}</ref> Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.<ref name="pmid18701488"/><ref name="pmid22201186">{{cite journal | vauthors = Marchand B, Tremblay I, Cagnol S, Boucher MJ | title = Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms | journal = Carcinogenesis | volume = 33 | issue = 3 | pages = 529–37 | date = March 2012 | pmid = 22201186 | doi = 10.1093/carcin/bgr309 }}</ref>


GSK-3 inhibitors have also shown promise in the treatment of T2DM.<ref name="pmid19366350"/> Though GSK-3 activity under diabetic conditions can differ radically across different tissue types, studies have shown that introducing competitive inhibitors of GSK-3 can increase glucose tolerance in diabetic mice.<ref name="pmid16944320"/> GSK-3 inhibitors may also have protective effects against transient cerebral ischemia and on hemorrhagic transformation after acute ischemic stroke.<ref name="pmid28553165">{{cite journal |vauthors=Wang W, Li M, Wang Y, Wang Z, Zhang W, Guan F, Chen Q, Wang J | title = GSK-3β as a target for protection against transient cerebral ischemia. | journal = Int J Med Sci. |date=Mar 2017 | pmid = 28553165 | doi = 10.7150/ijms.17514 | url =  }}</ref><ref name="pmid26671619">{{cite journal |vauthors=Wang W, Li M, Wang Y, Li Q, Deng G, Wan J, Yang Q, Chen Q, Wang J | title = GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats. | journal = Mol Neurobiol |date=Dec 2015 | pmid = 26671619 | doi = 10.1007/s12035-015-9607-2 | url = }}</ref> The role that inhibition of GSK-3 might play across its other signaling roles is not yet entirely understood.
GSK-3 inhibitors have also shown promise in the treatment of T2DM.<ref name="pmid19366350"/> Though GSK-3 activity under diabetic conditions can differ radically across different tissue types, studies have shown that introducing competitive inhibitors of GSK-3 can increase glucose tolerance in diabetic mice.<ref name="pmid16944320"/> GSK-3 inhibitors may also have therapeutic effects on hemorrhagic transformation after acute ischemic stroke.<ref name="pmid26671619">{{cite journal | vauthors = Wang W, Li M, Wang Y, Li Q, Deng G, Wan J, Yang Q, Chen Q, Wang J | title = GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats | journal = Molecular Neurobiology | volume = 53 | issue = 10 | pages = 7028–7036 | date = December 2016 | pmid = 26671619 | doi = 10.1007/s12035-015-9607-2 | pmc = 4909586 }}</ref> The role that inhibition of GSK-3 might play across its other signaling roles is not yet entirely understood.


GSK-3 inhibition also mediates an increase in the transcription of the transcription factor Tbet (Tbx21) and an inhibition of the transcription of the inhibitory co-receptor programmed cell death-1 (PD-1) on T-cells {{cite journal | vauthors = Taylor A, Harker J, Stevenson PG, Chanthong K, Zuniga EI, Rudd CE | title = Glycogen synthase kinase 3 (GSK-3α/β) regulates PD-1 expression via Tbet transcription for enhanced CD8+cytolytic T-cell response.| journal = Immunity |date= 2016 | pmid = 26885856 | volume= 44: 274-86}}. GSK-3 inhibitors increased in vivo CD8(+) OT-I CTL function and the clearance of viral infections by murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 as well as anti-PD-1 in immunotherapy.
GSK-3 inhibition also mediates an increase in the transcription of the transcription factor Tbet (Tbx21) and an inhibition of the transcription of the inhibitory co-receptor programmed cell death-1 (PD-1) on T-cells.<ref>{{cite journal | vauthors = Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, Rudd CE | title = Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses | journal = Immunity | volume = 44 | issue = 2 | pages = 274–86 | date = February 2016 | pmid = 26885856 | pmc = 4760122 | doi = 10.1016/j.immuni.2016.01.018 }}</ref> GSK-3 inhibitors increased in vivo CD8(+) OT-I CTL function and the clearance of viral infections by murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 as well as anti-PD-1 in immunotherapy.


== Inhibitors ==
== Inhibitors ==


Inhibitors of GSK-3 include:<ref name="pmid22065134">{{cite journal |vauthors=Eldar-Finkelman H, Martinez A | title = GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS | journal = Front Mol Neurosci | volume = 4 | issue = | pages = 32 | year = 2011 | pmid = 22065134 | pmc = 3204427 | doi = 10.3389/fnmol.2011.00032 }}</ref>
Inhibitors of GSK-3 include:<ref name="pmid22065134">{{cite journal | vauthors = Eldar-Finkelman H, Martinez A | title = GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS | journal = Frontiers in Molecular Neuroscience | volume = 4 | issue = | pages = 32 | year = 2011 | pmid = 22065134 | pmc = 3204427 | doi = 10.3389/fnmol.2011.00032 }}</ref>
{{colbegin|3}}
{{div col|colwidth=22em}}


===Metal cations===
===Metal cations===
Line 94: Line 95:
* [[Dibromocantharelline]] (IC<sub>50</sub>=3μM)
* [[Dibromocantharelline]] (IC<sub>50</sub>=3μM)
* [[Hymenialdesine]] (IC<sub>50</sub>=10nM)
* [[Hymenialdesine]] (IC<sub>50</sub>=10nM)
* [[Indirubins]] (IC<sub>50</sub>=5-50nM)
* [[Indirubin]] (IC<sub>50</sub>=5-50nM)
* [[Meridianins]]
* [[Meridianin]]


====Aminopyrimidines====
====Aminopyrimidines====
Line 139: Line 140:
====Peptides====
====Peptides====
* [[L803-mts]] (IC<sub>50</sub>=40μM)
* [[L803-mts]] (IC<sub>50</sub>=40μM)
{{colend}}
{{div col end}}


Other: Ketamine
Other: [[Ketamine]]


== See also ==
== See also ==
Line 147: Line 148:
* [[Tau-protein kinase]]
* [[Tau-protein kinase]]


==References==
== References ==
{{reflist|30em}}
{{reflist|32em}}


==External links==
== External links ==
* {{MeshName|Glycogen+Synthase+Kinase+3|3=Glycogen Synthase Kinase 3}}
* {{MeshName|Glycogen+Synthase+Kinase+3|3=Glycogen Synthase Kinase 3}}


Latest revision as of 16:30, 8 December 2018

glycogen synthase kinase 3 alpha
Identifiers
SymbolGSK3A
Entrez2931
HUGO4616
OMIM606784
RefSeqNM_019884
UniProtP49840
Other data
EC number2.7.11.26
LocusChr. 19 q13.2
glycogen synthase kinase 3 beta
File:1J1B.png
Crystallographic structure of human GSK-3β (rainbow colored, N-terminus = blue, C-terminus = red) bound to phosphoaminophosphonic acid-adenylate ester (spheres).[1]
Identifiers
SymbolGSK3B
Entrez2932
HUGO4617
OMIM605004
PDB1Q3W More structures
RefSeqNM_002093
UniProtP49841
Other data
EC number2.7.11.26
LocusChr. 3 q13.33

Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase,[2] GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways.[3] In mammals GSK-3 is encoded by two known genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder.

Mechanism

Active site of GSK-3
The active site of GSK-3. The three residues in blue bind the priming phosphate on the substrate, as demonstrated by the ligand. Residues D181, D200, K85, and E97.

GSK-3 functions by phosphorylating a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a "priming" phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, binds the terminal phosphate of ATP and transfers it to the target location on the substrate (see figure 1).[4]

Function

Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target.[5][6][7] 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.[2] After being primed by casein kinase 2 (CK2), glycogen synthase gets phosphorylated at a cluster of three C-terminal serine residues, reducing its activity.[8] 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 [9] and of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6 phosphatase.[10] However, these interactions have not been confirmed, as these pathways can be inhibited without the up-regulation of GSK-3.[8]

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.[11][12] 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.[12] 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.[11]

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.[13] GSK-3 is therefore a part of the canonical Beta-catenin/Wnt pathway, which signals the cell to divide and proliferate. GSK-3 also participates in a number of apoptotic signaling pathways by phosphorylating transcription factors that regulate apoptosis.[3] GSK-3 can promote apoptosis by both activating pro-apoptotic factors such as p53 [14] and inactivating survival-promoting factors through phosphorylation.[15] 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.[16] Overall, GSK-3 appears to both promote and inhibit apoptosis, and this regulation varies depending on the specific molecular and cellular context.[17]

Regulation

Due to its importance across numerous cellular functions, GSK-3 activity is subject to tight regulation.

The speed and efficacy of GSK-3 phosphorylation is regulated by a number of 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 serine-9 in GSK-3β or serine-21 in GSK-3α significantly decreases active site availability (see Figure 1).[11] 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.[8][18]

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,[19] 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.[11]

Disease relevance

Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in Alzheimer's disease, type 2 diabetes mellitus (T2DM), some forms of cancer, and bipolar disorder.[20]

It has now been shown that lithium, which is used as a treatment for bipolar disorder, acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition stabilizes mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect.[11] Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock.[21] Elements of the circadian clock may be connected with predisposition to bipolar mood disorder.[22]

GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of amyloid-β (Aβ) deposits and the formation of neurofibrillary tangles. GSK-3 is thought to directly promote Aβ production and to be tied to the process of the hyperphosphorylation of tau proteins, which leads to the tangles.[3][11] Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing.[23]

In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote apoptosis in some cases, it has also been reported to be a key factor in tumorigenesis in some cancers.[24] Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.[16][25]

GSK-3 inhibitors have also shown promise in the treatment of T2DM.[8] Though GSK-3 activity under diabetic conditions can differ radically across different tissue types, studies have shown that introducing competitive inhibitors of GSK-3 can increase glucose tolerance in diabetic mice.[11] GSK-3 inhibitors may also have therapeutic effects on hemorrhagic transformation after acute ischemic stroke.[26] The role that inhibition of GSK-3 might play across its other signaling roles is not yet entirely understood.

GSK-3 inhibition also mediates an increase in the transcription of the transcription factor Tbet (Tbx21) and an inhibition of the transcription of the inhibitory co-receptor programmed cell death-1 (PD-1) on T-cells.[27] GSK-3 inhibitors increased in vivo CD8(+) OT-I CTL function and the clearance of viral infections by murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 as well as anti-PD-1 in immunotherapy.

Inhibitors

Inhibitors of GSK-3 include:[28]

Metal cations

ATP-competitive

Marine organism-derived

Aminopyrimidines

IC50=0.6-7nM:

Arylindolemaleimide

Thiazoles

Paullones

IC50=4-80nM:

Aloisines

IC50=0.5-1.5μM:

Non-ATP competitive

Marine organism-derived

Thiadiazolidindiones

Halomethylketones

Peptides

Other: Ketamine

See also

References

  1. ↑ PDB: 1J1B​; Aoki M, Yokota T, Sugiura I, Sasaki C, Hasegawa T, Okumura C, Ishiguro K, Kohno T, Sugio S, Matsuzaki T (March 2004). "Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta". Acta Crystallographica Section D. 60 (Pt 3): 439–46. doi:10.1107/S090744490302938X. PMID 14993667.
  2. ↑ 2.0 2.1 Embi N, Rylatt DB, Cohen P (June 1980). "Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase". European Journal of Biochemistry. 107 (2): 519–27. doi:10.1111/j.1432-1033.1980.tb06059.x. PMID 6249596.
  3. ↑ 3.0 3.1 3.2 Jope RS, Johnson GV (February 2004). "The glamour and gloom of glycogen synthase kinase-3". Trends in Biochemical Sciences. 29 (2): 95–102. doi:10.1016/j.tibs.2003.12.004. PMID 15102436.
  4. ↑ Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH (June 2001). "Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition". Cell. 105 (6): 721–32. doi:10.1016/S0092-8674(01)00374-9. PMID 11440715.
  5. ↑ Woodgett JR (August 1994). "Regulation and functions of the glycogen synthase kinase-3 subfamily". Seminars in Cancer Biology. 5 (4): 269–75. PMID 7803763.
  6. ↑ Woodgett JR (September 2001). "Judging a protein by more than its name: GSK-3". Science's STKE. 2001 (100): re12. doi:10.1126/stke.2001.100.re12. PMID 11579232.
  7. ↑ Ali A, Hoeflich KP, Woodgett JR (August 2001). "Glycogen synthase kinase-3: properties, functions, and regulation". Chemical Reviews. 101 (8): 2527–40. doi:10.1021/cr000110o. PMID 11749387.
  8. ↑ 8.0 8.1 8.2 8.3 Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A (March 2009). "Glycogen synthase kinase 3: more than a namesake". British Journal of Pharmacology. 156 (6): 885–98. doi:10.1111/j.1476-5381.2008.00085.x. PMC 2697722. PMID 19366350.
  9. ↑ Liberman Z, Eldar-Finkelman H (February 2005). "Serine 332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling". The Journal of Biological Chemistry. 280 (6): 4422–8. doi:10.1074/jbc.M410610200. PMID 15574412.
  10. ↑ Lochhead PA, Coghlan M, Rice SQ, Sutherland C (May 2001). "Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression". Diabetes. 50 (5): 937–46. doi:10.2337/diabetes.50.5.937. PMID 11334436.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 Jope RS, Yuskaitis CJ, Beurel E (Apr–May 2007). "Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics". Neurochemical Research. 32 (4–5): 577–95. doi:10.1007/s11064-006-9128-5. PMC 1970866. PMID 16944320.
  12. ↑ 12.0 12.1 Wang H, Brown J, Martin M (February 2011). "Glycogen synthase kinase 3: a point of convergence for the host inflammatory response". Cytokine. 53 (2): 130–40. doi:10.1016/j.cyto.2010.10.009. PMC 3021641. PMID 21095632.
  13. ↑ Mills CN, Nowsheen S, Bonner JA, Yang ES (2011). "Emerging roles of glycogen synthase kinase 3 in the treatment of brain tumors". Frontiers in Molecular Neuroscience. 4: 47. doi:10.3389/fnmol.2011.00047. PMC 3223722. PMID 22275880.
  14. ↑ Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV, Jope RS (June 2002). "Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage". Proceedings of the National Academy of Sciences of the United States of America. 99 (12): 7951–5. doi:10.1073/pnas.122062299. PMC 123001. PMID 12048243.
  15. ↑ Grimes CA, Jope RS (September 2001). "CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium". Journal of Neurochemistry. 78 (6): 1219–32. doi:10.1046/j.1471-4159.2001.00495.x. PMC 1947002. PMID 11579131.
  16. ↑ 16.0 16.1 Kotliarova S, Pastorino S, Kovell LC, Kotliarov Y, Song H, Zhang W, Bailey R, Maric D, Zenklusen JC, Lee J, Fine HA (August 2008). "Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation". Cancer Research. 68 (16): 6643–51. doi:10.1158/0008-5472.CAN-08-0850. PMC 2585745. PMID 18701488.
  17. ↑ Jacobs KM, Bhave SR, Ferraro DJ, Jaboin JJ, Hallahan DE, Thotala D (May 2012). "GSK-3β: A Bifunctional Role in Cell Death Pathways". International Journal of Cell Biology. 2012: 930710. doi:10.1155/2012/930710. PMC 3364548. PMID 22675363.
  18. ↑ Doble BW, Woodgett JR (April 2003). "GSK-3: tricks of the trade for a multi-tasking kinase". Journal of Cell Science. 116 (Pt 7): 1175–86. doi:10.1242/jcs.00384. PMC 3006448. PMID 12615961.
  19. ↑ Bijur GN, Jope RS (December 2003). "Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria". NeuroReport. 14 (18): 2415–9. doi:10.1097/00001756-200312190-00025. PMID 14663202.
  20. ↑ Saraswati AP, Ali Hussaini SM, Krishna NH, Babu BN, Kamal A (January 2018). "Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions". European Journal of Medicinal Chemistry. 144: 843–858. doi:10.1016/j.ejmech.2017.11.103. PMID 29306837.
  21. ↑ Yin L, Wang J, Klein PS, Lazar MA (February 2006). "Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock". Science. 311 (5763): 1002–5. doi:10.1126/science.1121613. PMID 16484495.
  22. ↑ Rybakowski JK, Dmitrzak-Weglarz M, Dembinska-Krajewska D, Hauser J, Akiskal KK, Akiskal HH (April 2014). "Polymorphism of circadian clock genes and temperamental dimensions of the TEMPS-A in bipolar disorder". Journal of Affective Disorders. 159: 80–4. doi:10.1016/j.jad.2014.02.024. PMID 24679394.
  23. ↑ Hu S, Begum AN, Jones MR, Oh MS, Beech WK, Beech BH, Yang F, Chen P, Ubeda OJ, Kim PC, Davies P, Ma Q, Cole GM, Frautschy SA (February 2009). "GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals". Neurobiology of Disease. 33 (2): 193–206. doi:10.1016/j.nbd.2008.10.007. PMC 4313761. PMID 19038340.
  24. ↑ Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML (October 2008). "Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy". Nature. 455 (7217): 1205–9. doi:10.1038/nature07284. PMC 4084721. PMID 18806775.
  25. ↑ Marchand B, Tremblay I, Cagnol S, Boucher MJ (March 2012). "Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms". Carcinogenesis. 33 (3): 529–37. doi:10.1093/carcin/bgr309. PMID 22201186.
  26. ↑ Wang W, Li M, Wang Y, Li Q, Deng G, Wan J, Yang Q, Chen Q, Wang J (December 2016). "GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats". Molecular Neurobiology. 53 (10): 7028–7036. doi:10.1007/s12035-015-9607-2. PMC 4909586. PMID 26671619.
  27. ↑ Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, Rudd CE (February 2016). "Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses". Immunity. 44 (2): 274–86. doi:10.1016/j.immuni.2016.01.018. PMC 4760122. PMID 26885856.
  28. ↑ Eldar-Finkelman H, Martinez A (2011). "GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS". Frontiers in Molecular Neuroscience. 4: 32. doi:10.3389/fnmol.2011.00032. PMC 3204427. PMID 22065134.

External links

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