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
Glycogen 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
Regulacija 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
Fosforilacija 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
U 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)
Transkripcijski 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
Neurodegenerativne bolesti
GSK-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
GSK-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
Uloga 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
Pokazalo se da GSK3B stupa u interakciju sa:
- KIAA1211L[13]
Izvori
- ↑ "Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation". The Biochemical Journal 303 (Pt 3): 701–4. Studeni 1994.. doi:10.1042/bj3030701. PMC 1137602. PMID 7980435. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1137602/
- ↑ "Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter". Genomics 60 (2): 121–8. Rujan 1999.. doi:10.1006/geno.1999.5875. PMID 10486203
- ↑ "The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies". European Neuropsychopharmacology 20 (6): 357–68. Lipanj 2010.. doi:10.1016/j.euroneuro.2010.02.008. PMID 20226637
- ↑ Lua error in Modul:Citation/CS1 at line 4096: data for mw.loadData contains unsupported data type 'function'.
- ↑ Jope, Richard S.; Yuskaitis, Christopher J.; Beurel, Eléonore (30. kolovoz 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. http://dx.doi.org/10.1007/s11064-006-9128-5
- ↑ 6,0 6,1 Cho, Jae-Hyeon; Johnson, Gail V. W. (22. prosinac 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" (engl.). Journal of Neurochemistry 88 (2): 349–358. doi:10.1111/j.1471-4159.2004.02155.x. https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2004.02155.x
- ↑ Dajani, R. (3. veljača 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 PMC140752. PMID 12554650. http://emboj.embopress.org/cgi/doi/10.1093/emboj/cdg068
- ↑ Beals, Chan R.; Sheridan, Colleen M.; Turck, Christoph W.; Gardner, Phyllis; Crabtree, Gerald R. (28. ožujak 1997.). "Nuclear Export of NF-ATc Enhanced by Glycogen Synthase Kinase-3" (engl.). Science 275 (5308): 1930–1933. doi:10.1126/science.275.5308.1930. ISSN 0036-8075. https://www.science.org/doi/10.1126/science.275.5308.1930
- ↑ Lei, Peng; Ayton, Scott; Bush, Ashley I.; Adlard, Paul A. (4. svibanj 2011.). "GSK-3 in Neurodegenerative Diseases" [neaktivna poveznica] (engl.). International Journal of Alzheimer’s Disease 2011: e189246. doi:10.4061/2011/189246. ISSN 2090-8024. PMC PMC3100544. PMID 21629738. https://www.hindawi.com/journals/ijad/2011/189246/
- ↑ 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. PMID 35126052. https://www.frontiersin.org/article/10.3389/fnmol.2021.792364
- ↑ Leng, Sanhua; Zhang, Wenshuo; Zheng, Yanbin; Liberman, Ziva; Rhodes, Christopher J; Eldar-Finkelman, Hagit; Sun, Xiao Jian (1. 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 PMC3072280. PMID 20466847. https://joe.bioscientifica.com/view/journals/joe/206/2/171.xml
- ↑ Mancinelli, Romina; Carpino, Guido; Petrungaro, Simonetta; Mammola, Caterina Loredana; Tomaipitinca, Luana; Filippini, Antonio; Facchiano, Antonio; Ziparo, Elio et al. (2017). "Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases" (engl.). Oxidative Medicine and Cellular Longevity 2017: 1–14. doi:10.1155/2017/4629495. ISSN 1942-0900. PMC PMC5742885. PMID 29379583. https://www.hindawi.com/journals/omcl/2017/4629495/
- ↑ EMBL-EBI. "EMBL European Bioinformatics Institute" (engl.). http://www.ebi.ac.uk Pristupljeno 26. travanj 2017.
- ↑ 14,0 14,1 "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. Listopad 2002.. doi:10.1074/jbc.M206210200. PMID 12147701
- ↑ 15,0 15,1 "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". The Journal of Biological Chemistry 278 (8): 5947–51. Veljača 2003.. doi:10.1074/jbc.C200473200. PMID 12511557
- ↑ "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. Lipanj 1998.. doi:10.1046/j.1365-2443.1998.00198.x. PMID 9734785
- ↑ "Hot spots in beta-catenin for interactions with LEF-1, conductin and APC". Nature Structural Biology 7 (9): 800–7. Rujan 2000.. doi:10.1038/79039. PMID 10966653
- ↑ "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. Kolovoz 2002.. doi:10.1101/gad.230402. PMC 186448. PMID 12183362. //www.ncbi.nlm.nih.gov/pmc/articles/PMC186448/
- ↑ "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. Srpanj 2004.. doi:10.1074/jbc.M313963200. PMID 15178691
- ↑ "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. Travanj 2001.. doi:10.3892/ijo.18.4.843. PMID 11251183
- ↑ "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. Lipanj 1999.. doi:10.1128/mcb.19.6.4414. PMC 104400. PMID 10330181. //www.ncbi.nlm.nih.gov/pmc/articles/PMC104400/
- ↑ "Human dynamin-like protein interacts with the glycogen synthase kinase 3beta". Biochemical and Biophysical Research Communications 249 (3): 697–703. Kolovoz 1998.. doi:10.1006/bbrc.1998.9253. PMID 9731200
- ↑ "Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3β". Cell 144 (3): 341–52. Veljača 2011.. doi:10.1016/j.cell.2010.12.033. PMC 3050560. PMID 21295697. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3050560/
- ↑ "Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin". Molecular and Cellular Biology 18 (12): 7216–24. Prosinac 1998.. doi:10.1128/mcb.18.12.7216. PMC 109303. PMID 9819408. //www.ncbi.nlm.nih.gov/pmc/articles/PMC109303/
- ↑ "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. Ožujak 2001.. doi:10.1074/jbc.C000754200. PMID 11152665
- ↑ "Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling". Genes & Development 22 (1): 106–20. Siječanj 2008.. doi:10.1101/gad.1590908. PMC 2151009. PMID 18172167. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2151009/
- ↑ "Glycogen synthase kinase-3beta modulates notch signaling and stability". Current Biology 12 (12): 1006–11. Lipanj 2002.. doi:10.1016/S0960-9822(02)00888-6. PMID 12123574
- ↑ "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. Kolovoz 2003.. doi:10.1074/jbc.M304001200. PMID 12794074
- ↑ "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. Lipanj 2002.. Bibcode 2002PNAS...99.7951W. doi:10.1073/pnas.122062299. PMC 123001. PMID 12048243. //www.ncbi.nlm.nih.gov/pmc/articles/PMC123001/
- ↑ "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. Svibanj 2002.. doi:10.1016/S0006-291X(02)00349-2. PMID 12054501
- ↑ "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth". Cell 126 (5): 955–68. Rujan 2006.. doi:10.1016/j.cell.2006.06.055. PMID 16959574