RPS6KB1

RPS6KB1
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 3A60, 3A61, 3A62, 3WE4, 3WF5, 3WF6, 3WF7, 3WF8, 3WF9, 4L3J, 4L3L, 4L42, 4L43, 4L44, 4L45, 4L46, 4RLO, 4RLP
Identifikatori
Aliasi	RPS6KB1
Vanjski ID-jevi	OMIM: 608938 MGI: 1270849 HomoloGene: 81703 GeneCards: RPS6KB1
Lokacija gena (čovjek) Hrom. Hromosom 17 (čovjek)[1] Bend 17q23.1 Početak 59,893,046 bp[1] Kraj 59,950,574 bp[1]
Lokacija gena (miš) Hrom. Hromosom 11 (miš)[2] Bend 11|11 C Početak 86,498,871 bp[2] Kraj 86,544,805 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • aktivnost sa transferazom • protein kinase activity • nucleotide binding • peptide binding • GO:0001948, GO:0016582 vezivanje za proteine • vezivanje identičnih proteina • protein serine/threonine/tyrosine kinase activity • ATP binding • kinase activity • protein serine/threonine kinase activity • ribosomal protein S6 kinase activity • PDZ domain binding • protein phosphatase 2A binding Ćelijska komponenta • citoplazma • citosol • membrana • sinapsa • nukleoplazma • cell surface • mitochondrial outer membrane • međućelijske veze • mitohondrija • perinuklearno područje citoplazme • neuron projection • jedro Biološki proces • germ cell development • response to amino acid • response to glucagon • GO:1904578 response to organic cyclic compound • protein kinase B signaling • response to nutrient • Fosforilacija • regulation of glucose import • response to testosterone • negative regulation of extrinsic apoptotic signaling pathway • cellular response to growth factor stimulus • skeletal muscle contraction • response to mechanical stimulus • GO:0010260 starenje • response to leucine • GO:1904579 cellular response to organic cyclic compound • positive regulation of mitotic cell cycle • negative regulation of apoptotic process • response to heat • response to glucocorticoid • response to glucose • response to peptide hormone • behavioral fear response • positive regulation of translation • response to organic substance • positive regulation of smooth muscle cell migration • response to tumor necrosis factor • response to insulin • response to lipopolysaccharide • GO:1903105 negative regulation of insulin receptor signaling pathway • cellular response to hormone stimulus • Dugoročno pamćenje • response to wounding • response to organonitrogen compound • response to electrical stimulus involved in regulation of muscle adaptation • skeletal muscle atrophy • ćelijski ciklus • response to ethanol • positive regulation of translational initiation • Ćelijska migracija • response to toxic substance • positive regulation of skeletal muscle tissue growth • regulation of translation • phosphatidylinositol-mediated signaling • GO:0072468 Transdukcija signala • positive regulation of smooth muscle cell proliferation • GO:0097285 apoptoza • protein phosphorylation • cellular response to dexamethasone stimulus • cellular response to insulin stimulus • G1/S transition of mitotic cell cycle • GO:0035404 peptidyl-serine phosphorylation • TOR signaling • cellular response to interferon-gamma • long-chain fatty acid import into cell • GO:0007243 intracellular signal transduction • response to nutrient levels Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	6198	72508
Ensembl	ENSG00000108443	ENSMUSG00000020516
UniProt	P23443	Q8BSK8
RefSeq (mRNK)	NM_001272042 NM_001272043 NM_001272044 NM_001272060 NM_003161	NM_001114334 NM_028259 NM_001363162
RefSeq (bjelančevina)	NP_001258971 NP_001258972 NP_001258973 NP_001258989 NP_003152 NP_001356598 NP_001356599 NP_001356600 NP_001356601 NP_001356602 NP_001356603 NP_001356604 NP_001356605 NP_001356606 NP_001356607 NP_001356608	NP_001107806 NP_082535 NP_001350091
Lokacija (UCSC)	Chr 17: 59.89 – 59.95 Mb	Chr 11: 86.5 – 86.54 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Ribosomna protein S6 kinaza beta-1 (S6K1), znana i kao p70S6 kinaza (p70S6K, p70-S6K), je enzim (preciznije protein-kinaza) koji je kod ljudi kodiran genom RPS6KB1.^[5][6] To je serin / treonin kinaza koja djeluje nizvodno od PIP3 i fosfoinozitid-ovisne kinaze-1 u PI3 kinaznom putu.^[7] Kao što i samo ime govori, njegov cilj supstrat je ribosomski protein S6.^[8] Sintezu proteina na ribosomu nducira fosforilacija S6.

Fosforilacija p70S6K na treoninu 389 korištena je kao obilježje aktivacije od mTOR i u korelaciji je s inhibicijom autofagija u različitim situacijama. Međutim, nekoliko nedavnih studija sugerira da aktivnost p70S6K ima pozitivniju ulogu u porastu autofagije.^[9][10]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 525 aminokiselina, a molekulska težina 59.140 Da.^[11].

10		20		30		40		50
MRRRRRRDGF		YPAPDFRDRE		AEDMAGVFDI		DLDQPEDAGS		EDELEEGGQL
NESMDHGGVG		PYELGMEHCE		KFEISETSVN		RGPEKIRPEC		FELLRVLGKG
GYGKVFQVRK		VTGANTGKIF		AMKVLKKAMI		VRNAKDTAHT		KAERNILEEV
KHPFIVDLIY		AFQTGGKLYL		ILEYLSGGEL		FMQLEREGIF		MEDTACFYLA
EISMALGHLH		QKGIIYRDLK		PENIMLNHQG		HVKLTDFGLC		KESIHDGTVT
HTFCGTIEYM		APEILMRSGH		NRAVDWWSLG		ALMYDMLTGA		PPFTGENRKK
TIDKILKCKL		NLPPYLTQEA		RDLLKKLLKR		NAASRLGAGP		GDAGEVQAHP
FFRHINWEEL		LARKVEPPFK		PLLQSEEDVS		QFDSKFTRQT		PVDSPDDSTL
SESANQVFLG		FTYVAPSVLE		SVKEKFSFEP		KIRSPRRFIG		SPRTPVSPVK
FSPGDFWGRG		ASASTANPQT		PVEYPMETSG		IEQMDVTMSG		EASAPLPIRQ
PNSGPYKKQA		FPMISKRPEH		LRMNL

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Funkcija

Ovaj gen kodira člana RSK porodice serin / treonin kinaza. Ova kinaza sadrži dva neidentična katalitska domena kinaze i fosforilira nekoliko ostataka ribosomskog proteina S6. Aktivnost kinaze ovog proteina dovodi do povećanja sinteze proteina i proliferacije ćelija. Pojačanje regije DNK koja kodira ovaj gen i prekomerna ekspresija ove kinaze uočene su u nekim ćelijskim linijama karcinoma dojke. Opisana su alternativna mjesta translacije i varijante prerađenih transkripata, ali nisu detaljno okarakterizirana.

mTOR

P70S6 kinaza je nizvodna meta signalizacije mTOR (cilj sisarskog rapamicina), posebno mTORC1, kompleksa koji sadrži mTOR, a karakterizira se uključivanjem Raptora, a ne Riktora (mTORC2). mTOR se može aktivirati putem mehanizma sličnog AND-vratima u lizosomu, integrirajući signale o faktorima rasta i bioraspoloživosti važnih molekula. Naprimjer, aminokiseline poput arginina i leucina mogu podstaknuti lizosomsko regrutiranje mTORC1. Kada se nađe u lizosomu, mTOR može aktivirati Rheb, malu GTPazu, koja se nalazi u lizosomu, u svom stanju vezanom za GTP. Aktivnost reb GTPaze stimulira (i samim tim smanjuje kapacitet za aktiviranje mTOR) uzvodnim TSC kompleksom, koji je inhibiran IGF signalizacijom. Stoga se AND ulaz sastoji od pravilne lokalizacije dovoljnom količinom aminokiselina i aktivacije faktorima rasta. Jednom kada je mTOR pravilno lokaliziran i aktiviran, može fosforilirati nizvodne ciljeve kao što su p70S6K, 4EBP i ULK1, koji su važni za regulaciju anaboličke/ kataboličke ravnoteže proteina. Fizička vježba aktivira sintezu proteina, fosforilacijom (aktivacijom) p70S6K na putu koji ovisi o mTOR, konkretno mTORC1. To je dokazano upotrebom inhibitora mTOR-a, rapamicina, za blokiranje povećanja mišićne mase, uprkos povećanom opterećenju (npr. vježbanjem). Pokazalo se da vježba povećava nivo IGF-1 u mišićima, indukujući tako signalni put IGF-1/PI3K/Akt/p70S6K, a samim tim povećanu sintezu proteina potrebnih za izgradnju mišića.

Klinički značaj

Inhibicija proteina S6K1, ili njegov nedostatak, usporava proizvodnju masnih ćelija, ometanjem i usporavanjem početne "faze posvećenosti" njihovom formiranju. Studija bi mogla imati implikacije na liječenje gojaznosti.^[12]

Amplifikacija regije DNK koja kodira ovaj gen i prekomerna ekspresija ove kinaze uočena je kod nekih karcinoma dojke u ćelijskim linijama.

Sljedeći put, za koji je P70 predložio njegovosudjelovanje, produžuje i rast mišića. P70 se fosforilira pasivnim istezanjem u mišićima. Ovo je možda jedna od mnogih proteinskih kinaza uključenih u izgradnju mišića.^[13]

U svom neaktivnom stanju, S6K1 je vezan za eIF3 i odvaja se nakon fosforilacije, pomoću mTOR/Raptor-a. Slobodni S6K1 tada može fosforilirati svoje brojne ciljeve, uključujući eIF4B.^[14]

Interakcije

Pokazano je da P70-S6 kinaza 1 komunicira sa:

• COASY,^[15]
• CSNK2B,^[16]
• EIF3B,^[17]
• KIAA1303,^{[18][19][20][21]}
• MTOR,^{[22][23][24][25][26][27][28][29][30][31][32][33]}
• POLDIP3,^[34]
• PPP2R2A,^[35][36]
• RBX1,^[37] i
• UBC.^[37]

Također pogledajte

• Ribosomna S6 kinaza
• RPS6KA1

Reference

1. GRCh38: Ensembl release 89: ENSG00000108443 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020516 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Grove JR, Banerjee P, Balasubramanyam A, Coffer PJ, Price DJ, Avruch J, Woodgett JR (Nov 1991). "Cloning and expression of two human p70 S6 kinase polypeptides differing only at their amino termini". Molecular and Cellular Biology. 11 (11): 5541–50. doi:10.1128/mcb.11.11.5541. PMC 361924. PMID 1922062.
6. "Entrez Gene: RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1".
7. Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J. (1994). "PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase". Nature. 370 (6484): 71–75. doi:10.1038/370071a0. PMID 8015612. S2CID 4352132.
8. Chung J, Kuo CJ, Crabtree GR, Blenis J. (1992). "Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases". Cell. 69 (7): 1227–1236. doi:10.1016/0092-8674(92)90643-Q. PMID 1377606. S2CID 31812410.
9. Datan E, Shirazian A, Benjamin S, Matassov D, Tinari A, Malorni W, Lockshin RA, Garcia-Sastre A, Zakeri Z (2014). "mTOR/p70s6k signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza infection". Virology. 452–453 (march 2014): 175–190. doi:10.1016/j.virol.2014.01.008. PMC 4005847. PMID 24606695.
10. Ci Y, Shi K, An J, Yang Y, Hui K, Wu P, Shi L, Xu C (2014). "ROS inhibit autophagy by downregulating ULK1 mediated by the phosphorylation of p53 in selenite-treated NB4 cells". Cell Death and Disease. 5 (November 2014): 1–10. doi:10.1038/cddis.2014.506. PMC 4260759. PMID 25429619.
11. "UniProt, P23443". Pristupljeno June 25, 2021.
12. Carnevalli LS, Masuda K, Frigerio F, Le Bacquer O, Um SH, Gandin V, Topisirovic I, Sonenberg N, Thomas G, Kozma SC (maj 2010). "S6K1 plays a critical role in early adipocyte differentiation". Developmental Cell. 18 (5): 763–74. doi:10.1016/j.devcel.2010.02.018. PMC 2918254. PMID 20493810.
13. Van Dyke JM, Bain JL, Riley DA (Jan 2014). "Stretch-activated signaling is modulated by stretch magnitude and contraction". Muscle & Nerve. 49 (1): 98–107. doi:10.1002/mus.23880. PMID 23620271. S2CID 206294774.
14. Holz, Marina K.; Ballif, Bryan A.; Gygi, Steven P.; Blenis, John (2005). "mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events". Cell. 123 (4): 569–580. doi:10.1016/j.cell.2005.10.024. PMID 16286006. S2CID 11118504. Pristupljeno 1. 3. 2016.
15. Nemazanyy I, Panasyuk G, Zhyvoloup A, Panayotou G, Gout IT, Filonenko V (Dec 2004). "Specific interaction between S6K1 and CoA synthase: a potential link between the mTOR/S6K pathway, CoA biosynthesis and energy metabolism". FEBS Letters. 578 (3): 357–62. doi:10.1016/j.febslet.2004.10.091. PMID 15589845. S2CID 9916948.
16. Panasyuk G, Nemazanyy I, Zhyvoloup A, Bretner M, Litchfield DW, Filonenko V, Gout IT (Oct 2006). "Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17". The Journal of Biological Chemistry. 281 (42): 31188–201. doi:10.1074/jbc.M602618200. PMID 16895915.
17. Holz MK, Ballif BA, Gygi SP, Blenis J (Nov 2005). "mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events". Cell. 123 (4): 569–80. doi:10.1016/j.cell.2005.10.024. PMID 16286006. S2CID 11118504.
18. Ali SM, Sabatini DM (maj 2005). "Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site". The Journal of Biological Chemistry. 280 (20): 19445–8. doi:10.1074/jbc.C500125200. PMID 15809305.
19. Ha SH, Kim DH, Kim IS, Kim JH, Lee MN, Lee HJ, Kim JH, Jang SK, Suh PG, Ryu SH (Dec 2006). "PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals". Cellular Signalling. 18 (12): 2283–91. doi:10.1016/j.cellsig.2006.05.021. PMID 16837165.
20. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (Jul 2002). "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action". Cell. 110 (2): 177–89. doi:10.1016/S0092-8674(02)00833-4. PMID 12150926. S2CID 6438316.
21. Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K (maj 2003). "The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif". The Journal of Biological Chemistry. 278 (18): 15461–4. doi:10.1074/jbc.C200665200. PMID 12604610.
22. Chiang GG, Abraham RT (Jul 2005). "Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase". The Journal of Biological Chemistry. 280 (27): 25485–90. doi:10.1074/jbc.M501707200. PMID 15899889.
23. Holz MK, Blenis J (Jul 2005). "Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase". The Journal of Biological Chemistry. 280 (28): 26089–93. doi:10.1074/jbc.M504045200. PMID 15905173.
24. Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K (Nov 1999). "Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro". The Journal of Biological Chemistry. 274 (48): 34493–8. doi:10.1074/jbc.274.48.34493. PMID 10567431.
25. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (Apr 2005). "Rheb binds and regulates the mTOR kinase". Current Biology. 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. PMID 15854902. S2CID 3078706.
26. Toral-Barza L, Zhang WG, Lamison C, Larocque J, Gibbons J, Yu K (Jun 2005). "Characterization of the cloned full-length and a truncated human target of rapamycin: activity, specificity, and enzyme inhibition as studied by a high capacity assay". Biochemical and Biophysical Research Communications. 332 (1): 304–10. doi:10.1016/j.bbrc.2005.04.117. PMID 15896331.
27. Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis PB, Thomas G (maj 2002). "Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site". The Journal of Biological Chemistry. 277 (22): 20104–12. doi:10.1074/jbc.M201745200. PMID 11914378.
28. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (Jul 2002). "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery". Cell. 110 (2): 163–75. doi:10.1016/S0092-8674(02)00808-5. PMID 12150925. S2CID 4656930.
29. Edinger AL, Linardic CM, Chiang GG, Thompson CB, Abraham RT (Dec 2003). "Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells". Cancer Research. 63 (23): 8451–60. PMID 14679009.
30. Leone M, Crowell KJ, Chen J, Jung D, Chiang GG, Sareth S, Abraham RT, Pellecchia M (Aug 2006). "The FRB domain of mTOR: NMR solution structure and inhibitor design". Biochemistry. 45 (34): 10294–302. doi:10.1021/bi060976+. PMID 16922504.
31. Takahashi T, Hara K, Inoue H, Kawa Y, Tokunaga C, Hidayat S, Yoshino K, Kuroda Y, Yonezawa K (Sep 2000). "Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and in vitro". Genes to Cells. 5 (9): 765–75. doi:10.1046/j.1365-2443.2000.00365.x. PMID 10971657. S2CID 39048740.
32. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (Feb 1998). "RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1". Proceedings of the National Academy of Sciences of the United States of America. 95 (4): 1432–7. doi:10.1073/pnas.95.4.1432. PMC 19032. PMID 9465032.
33. Sarbassov DD, Sabatini DM (Nov 2005). "Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex". The Journal of Biological Chemistry. 280 (47): 39505–9. doi:10.1074/jbc.M506096200. PMID 16183647.
34. Richardson CJ, Bröenstrup M, Fingar DC, Jülich K, Ballif BA, Gygi S, Blenis J (Sep 2004). "SKAR is a specific target of S6 kinase 1 in cell growth control". Current Biology. 14 (17): 1540–9. doi:10.1016/j.cub.2004.08.061. PMID 15341740. S2CID 12838409.
35. Peterson RT, Desai BN, Hardwick JS, Schreiber SL (Apr 1999). "Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein". Proceedings of the National Academy of Sciences of the United States of America. 96 (8): 4438–42. doi:10.1073/pnas.96.8.4438. PMC 16350. PMID 10200280.
36. Bishop JD, Nien WL, Dauphinee SM, Too CK (Aug 2006). "Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells". The Journal of Endocrinology. 190 (2): 307–12. doi:10.1677/joe.1.06368. PMID 16899564.
37. Panasyuk G, Nemazanyy I, Filonenko V, Gout I (maj 2008). "Ribosomal protein S6 kinase 1 interacts with and is ubiquitinated by ubiquitin ligase ROC1". Biochemical and Biophysical Research Communications. 369 (2): 339–43. doi:10.1016/j.bbrc.2008.02.016. PMID 18279656.

Vanjski linkovi

• P23443

Portal Biologija