Kinaza glikogen sintaze-3 beta
Kinaza glikogen sintaze -3 beta, ( eng. Glycogen synthase kinase-3 beta, GSK-3 beta) je enzim koji je kod ljudi kodiran genom GSK3B i sastoji se od dvije kinazne domene.[1][2] Kod miševa, enzim je kodiran genom Gsk3b. Abnormalna regulacija i ekspresija GSK-3 beta povezana je s povećanom osjetljivošću na bipolarni poremećaj i neka druga patološka stanja, s naglaskom na mentalne i neurodegenerativne bolesti.[3]
Struktura
urediGlycogen synthase kinase 3 (GSK3) je serin-treonin kinaza koja se sastoji od tri različite izoforme; GSK3-α, GSK3-β, i jedne, puno različitije od prvih dviju - GSK3-β2. Dok se GSK3-α može naći pretežito u astrocitama i endotelnim stanicama, GSK3-β se eksprimira u mozgu, velikim dijelom u atrocitama i neuronima kod ljudi, a kod miševa i u endotelnim stanicama.[4]
GSK3-ß sastoji se od dvije kinazne domene. Domena s ß-pločom nalazi se na N-terminalnom kraju (AA 25-138), dok je dio s α-uzvojnicom na C-terminalnom kraju (AA 139-349).[5]
Funkcije
urediRegulacija GSK-3 važna je za normalan razvoj, regulaciju metabolizma, rast neurona i diferencijaciju te modulaciju stanične smrti. Razlog tomu je što je prisutan u većem dijelu stanice te ima utjecaj na mnoge procese u stanici.
Interakcija s tau proteinom
urediFosforilacija tau-a na specifičnom mjestu negativno regulira njegovu sposobnost vezanja i stabilizacije strukture mikrotubula. GSK3beta fosforilira i primirana i neprimirana mjesta na tau, ali samo fosforilacija na primiranim mjestima značajno smanjuje sposobnost tau-a da veže mikrotubule.[6]
GSK3β fosforilacija Thr231 u tau, koji je primirano mjesto fosforilacije, igra ključnu ulogu u smanjenju povezanosti taua s citoskeletom.[6]
Wnt signalizacija
urediU Wnt signalizaciji GSK3B tvori multimerni kompleks s nekoliko drugih proteina i fosforilira N-terminus beta-katenina što dovodi do njegove razgradnje posredovane ubikvitinom/proteasomima.[7]
Interakcija s kalcineurinom (NFATC put)
urediTranskripcijski faktor NF-AT reagira na Ca2+-kalcineurinske signale translokacijom u jezgru, gdje sudjeluje u aktivaciji gena ranog imunološkog odgovora. Kalcineurin defosforilira konzervirane serinske ostatke u amino terminusu NF-AT, što rezultira nuklearnim uvozom. GSK-3 fosforilira konzervirane serine potrebne za nuklearni izvoz, potiče izlazak iz jezgre i time se suprotstavlja Ca2+-kalcineurinskom signaliziranju.[8]
Značaj GSK-3β u bolestima
urediNeurodegenerativne bolesti
urediGSK-3β stupa u interakciju s tau, β-amiloidom (Aβ) i α-sinukleinom te je kao takav uključen u patogenezu Alzheimerove i Parkinsonove bolesti. GSK-3β regulira proizvodnju β-amiloida, a njegova toksičnost je posredovana induciranom tau fosforilacijom i degeneracijom. α-sinuklein je supstrat za GSK-3β, a njegova inhibicija sprječava Aβ-induciranu toksičnost za neurone u Parkinsonovoj bolesti.[9]
Uočeno je da litij, koji se koristi za liječenje bipolarnih poremećaja, inhibira GSK-3β, što je ovaj enzim učinilo važnom metom za liječenje poremećaja raspoloženja.[10]
Dijabetes
urediGSK-3β je negativno reguliran inzulinom, a njegova inhibicija poboljšava djelovanje inzulina i metabolizam glukoze. GSK3β izravno fosforilira IRS1 (supstrat inzulinskog receptora 1) in vitro i in vivo na serin332 i ometa inzulinsku signalizaciju.[11]
Rak
urediUloga GSK-3β u napredovanju raka je još uvijek nejasna. Uočeno je da inhibicija GSK-3β dovodi do aktivacije β-katenina i proliferacije stanica što u konačnici dovodi do nastanka tumora.[12]
Interakcije
urediPokazalo se da GSK3B stupa u interakciju sa:
- KIAA1211L[13]
Izvori
uredi- ↑ Stambolic V, Woodgett JR. Studeni 1994. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. The Biochemical Journal. 303 (Pt 3): 701–4. doi:10.1042/bj3030701. PMC 1137602. PMID 7980435
- ↑ Lau KF, Miller CC, Anderton BH, Shaw PC. Rujan 1999. Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter. Genomics. 60 (2): 121–8. doi:10.1006/geno.1999.5875. PMID 10486203
- ↑ Luykx JJ, Boks MP, Terwindt AP, Bakker S, Kahn RS, Ophoff RA. Lipanj 2010. The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies. European Neuropsychopharmacology. 20 (6): 357–68. doi:10.1016/j.euroneuro.2010.02.008. PMID 20226637
- ↑ Chaney, Aisling M.; Deal, Emily M.; Jackson, Isaac M.; James, Michelle L. 1. siječnja 2021. Ross, Brian D.; Gambhir, Sanjiv Sam (ur.). Chapter 68 - PET Imaging of Neuroinflammation (engleski). Academic Press. str. 1335–1371. ISBN 978-0-12-816386-3
- ↑ Jope, Richard S.; Yuskaitis, Christopher J.; Beurel, Eléonore. 30. kolovoza 2006. Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics. Neurochemical Research. 32 (4–5): 577–595. doi:10.1007/s11064-006-9128-5. ISSN 0364-3190
- ↑ a b Cho, Jae-Hyeon; Johnson, Gail V. W. 22. prosinca 2003. Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau's ability to bind and stabilize microtubules: Phosphorylation of Thr231 on tau inhibits function. Journal of Neurochemistry (engleski). 88 (2): 349–358. doi:10.1111/j.1471-4159.2004.02155.x
- ↑ Dajani, R. 3. veljače 2003. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. The EMBO Journal. 22 (3): 494–501. doi:10.1093/emboj/cdg068. PMC 140752. PMID 12554650CS1 održavanje: format PMC-a (link)
- ↑ Beals, Chan R.; Sheridan, Colleen M.; Turck, Christoph W.; Gardner, Phyllis; Crabtree, Gerald R. 28. ožujka 1997. Nuclear Export of NF-ATc Enhanced by Glycogen Synthase Kinase-3. Science (engleski). 275 (5308): 1930–1933. doi:10.1126/science.275.5308.1930. ISSN 0036-8075
- ↑ Lei, Peng; Ayton, Scott; Bush, Ashley I.; Adlard, Paul A. 4. svibnja 2011. GSK-3 in Neurodegenerative Diseases. International Journal of Alzheimer’s Disease (engleski). 2011: e189246. doi:10.4061/2011/189246. ISSN 2090-8024. PMC 3100544. PMID 21629738
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(pomoć)CS1 održavanje: format PMC-a (link) - ↑ Arciniegas Ruiz, Sara Melisa; Eldar-Finkelman, Hagit. 2022. Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward. Frontiers in Molecular Neuroscience. 14. doi:10.3389/fnmol.2021.792364. ISSN 1662-5099. PMC PMC8813766 Provjerite vrijednost parametra
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(pomoć). PMID 35126052 Provjerite vrijednost parametra|pmid=
(pomoć)CS1 održavanje: format PMC-a (link) - ↑ Leng, Sanhua; Zhang, Wenshuo; Zheng, Yanbin; Liberman, Ziva; Rhodes, Christopher J; Eldar-Finkelman, Hagit; Sun, Xiao Jian. Kolovoz 2010. Glycogen synthase kinase 3β mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. Journal of Endocrinology. 206 (2): 171–181. doi:10.1677/JOE-09-0456. ISSN 0022-0795. PMC 3072280. PMID 20466847CS1 održavanje: format PMC-a (link)
- ↑ Mancinelli, Romina; Carpino, Guido; Petrungaro, Simonetta; Mammola, Caterina Loredana; Tomaipitinca, Luana; Filippini, Antonio; Facchiano, Antonio; Ziparo, Elio; Giampietri, Claudia. 2017. Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases. Oxidative Medicine and Cellular Longevity (engleski). 2017: 1–14. doi:10.1155/2017/4629495. ISSN 1942-0900. PMC 5742885. PMID 29379583CS1 održavanje: format PMC-a (link)
- ↑ EMBL-EBI. EMBL European Bioinformatics Institute. www.ebi.ac.uk (engleski). Pristupljeno 26. travnja 2017.
- ↑ a b Tanji C, Yamamoto H, Yorioka N, Kohno N, Kikuchi K, Kikuchi A. Listopad 2002. A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent inhibition of GSK-3beta. The Journal of Biological Chemistry. 277 (40): 36955–61. doi:10.1074/jbc.M206210200. PMID 12147701
- ↑ a b Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS. Veljača 2003. The tuberin-hamartin complex negatively regulates beta-catenin signaling activity. The Journal of Biological Chemistry. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMID 12511557
- ↑ Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T. Lipanj 1998. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level. Genes to Cells. 3 (6): 395–403. doi:10.1046/j.1365-2443.1998.00198.x. PMID 9734785. S2CID 10875463
- ↑ von Kries JP, Winbeck G, Asbrand C, Schwarz-Romond T, Sochnikova N, Dell'Oro A, Behrens J, Birchmeier W. Rujan 2000. Hot spots in beta-catenin for interactions with LEF-1, conductin and APC. Nature Structural Biology. 7 (9): 800–7. doi:10.1038/79039. PMID 10966653. S2CID 40432152
- ↑ Schwarz-Romond T, Asbrand C, Bakkers J, Kühl M, Schaeffer HJ, Huelsken J, Behrens J, Hammerschmidt M, Birchmeier W. Kolovoz 2002. The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes & Development. 16 (16): 2073–84. doi:10.1101/gad.230402. PMC 186448. PMID 12183362
- ↑ Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C. Srpanj 2004. Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells. The Journal of Biological Chemistry. 279 (31): 32444–52. doi:10.1074/jbc.M313963200. PMID 15178691
- ↑ Davies G, Jiang WG, Mason MD. Travanj 2001. The interaction between beta-catenin, GSK3beta and APC after motogen induced cell-cell dissociation, and their involvement in signal transduction pathways in prostate cancer. International Journal of Oncology. 18 (4): 843–7. doi:10.3892/ijo.18.4.843. PMID 11251183
- ↑ Kishida S, Yamamoto H, Hino S, Ikeda S, Kishida M, Kikuchi A. Lipanj 1999. DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability. Molecular and Cellular Biology. 19 (6): 4414–22. doi:10.1128/mcb.19.6.4414. PMC 104400. PMID 10330181
- ↑ Hong YR, Chen CH, Cheng DS, Howng SL, Chow CC. Kolovoz 1998. Human dynamin-like protein interacts with the glycogen synthase kinase 3beta. Biochemical and Biophysical Research Communications. 249 (3): 697–703. doi:10.1006/bbrc.1998.9253. PMID 9731200
- ↑ Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, Fuchs E. Veljača 2011. Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3β. Cell. 144 (3): 341–52. doi:10.1016/j.cell.2010.12.033. PMC 3050560. PMID 21295697
- ↑ Li Y, Bharti A, Chen D, Gong J, Kufe D. Prosinac 1998. Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin. Molecular and Cellular Biology. 18 (12): 7216–24. doi:10.1128/mcb.18.12.7216. PMC 109303. PMID 9819408
- ↑ Li Y, Kuwahara H, Ren J, Wen G, Kufe D. Ožujak 2001. The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin. The Journal of Biological Chemistry. 276 (9): 6061–4. doi:10.1074/jbc.C000754200. PMID 11152665
- ↑ Guo X, Ramirez A, Waddell DS, Li Z, Liu X, Wang XF. Siječanj 2008. Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. Genes & Development. 22 (1): 106–20. doi:10.1101/gad.1590908. PMC 2151009. PMID 18172167
- ↑ Foltz DR, Santiago MC, Berechid BE, Nye JS. Lipanj 2002. Glycogen synthase kinase-3beta modulates notch signaling and stability. Current Biology. 12 (12): 1006–11. doi:10.1016/S0960-9822(02)00888-6. PMID 12123574. S2CID 15884556
- ↑ Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A. Kolovoz 2003. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. The Journal of Biological Chemistry. 278 (34): 32227–35. doi:10.1074/jbc.M304001200. PMID 12794074
- ↑ Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV, Jope RS. Lipanj 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. Bibcode:2002PNAS...99.7951W. doi:10.1073/pnas.122062299. PMC 123001. PMID 12048243
- ↑ Dai F, Yu L, He H, Chen Y, Yu J, Yang Y, Xu Y, Ling W, Zhao S. Svibanj 2002. Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction. Biochemical and Biophysical Research Communications. 293 (4): 1191–6. doi:10.1016/S0006-291X(02)00349-2. PMID 12054501
- ↑ Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL. Rujan 2006. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 126 (5): 955–68. doi:10.1016/j.cell.2006.06.055. PMID 16959574. S2CID 16047397