P70-S6 Kinase 1

Ribosomal protein S6 kinase, 70kDa, polypeptide 1
Rendering based on PDB 3A60​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3A60​, 3A61​, 3A62​, 3WE4​, 3WF5​, 3WF6​, 3WF7​, 3WF8​, 3WF9​, 4L3J​, 4L3L​, 4L42​, 4L43​, 4L44​, 4L45​, 4L46​, 4RLO​, 4RLP​
Identifiers
Symbols	RPS6KB1 ; PS6K; S6K; S6K-beta-1; S6K1; STK14A; p70 S6KA; p70(S6K)-alpha; p70-S6K; p70-alpha
External IDs	OMIM: 608938 HomoloGene: 81703 ChEMBL: 4501 GeneCards: RPS6KB1 Gene
EC number	2.7.11.1
Gene ontology Molecular function • protein kinase activity • ribosomal protein S6 kinase activity • protein serine/threonine/tyrosine kinase activity • protein binding • ATP binding • peptide binding • protein phosphatase 2A binding Cellular component • nucleus • nucleoplasm • cytoplasm • mitochondrion • mitochondrial outer membrane • cytosol • cell surface • cell junction • neuron projection • synapse • perinuclear region of cytoplasm Biological process • G1/S transition of mitotic cell cycle • behavioral fear response • skeletal muscle contraction • protein phosphorylation • apoptotic process • signal transduction • germ cell development • aging • response to nutrient • long-term memory • insulin receptor signaling pathway • response to heat • response to wounding • response to mechanical stimulus • response to toxic substance • response to glucose • skeletal muscle atrophy • response to electrical stimulus involved in regulation of muscle adaptation • positive regulation of smooth muscle cell migration • cell migration • TOR signaling • response to lipopolysaccharide • cellular response to insulin stimulus • response to testosterone • response to glucagon • response to tumor necrosis factor • response to drug • negative regulation of apoptotic process • response to leucine • protein kinase B signaling • response to ethanol • positive regulation of translation • positive regulation of mitotic cell cycle • positive regulation of translational initiation • regulation of glucose import • negative regulation of insulin receptor signaling pathway • phosphatidylinositol-mediated signaling • positive regulation of skeletal muscle tissue growth • positive regulation of smooth muscle cell proliferation • response to glucocorticoid • cellular response to growth factor stimulus • cellular response to organic cyclic compound • negative regulation of extrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6198	72508
Ensembl	ENSG00000108443	ENSMUSG00000020516
UniProt	P23443	Q8BSK8
RefSeq (mRNA)	NM_001272042	NM_001114334
RefSeq (protein)	NP_001258971	NP_001107806
Location (UCSC)	Chr 17: 59.89 – 59.95 Mb	Chr 11: 86.5 – 86.54 Mb
PubMed search

Ribosomal protein S6 kinase beta-1 (S6K1) is an enzyme that in humans is encoded by the RPS6KB1 gene.^[1][2]

Function

This gene encodes a member of the RSK family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates several residues of the S6 ribosomal protein. The kinase activity of this protein leads to an increase in protein synthesis and cell proliferation. Amplification of the region of DNA encoding this gene and overexpression of this kinase are seen in some breast cancer cell lines. Alternate translational start sites have been described and alternate transcriptional splice variants have been observed but have not been thoroughly characterized.

Clinical significance

Inhibition of the S6K1 protein, or a lack of it, slows the production of adipose (fat) cells by disrupting and retarding the initial "commitment stage" of their formation. The study could have implications for the treatment of obesity.^[3]

Amplification of the region of DNA encoding this gene and overexpression of this kinase are seen in some breast cancer cell lines.

Another pathway for which P70 has proposed involvement is in muscle lengthening and growing. P70 is phosphorylated by passive stretch in the soleus muscle. This may be one of many protein kinases involved in muscle building.^[4]

In its inactive state, S6K1 is bound to eIF3 and detaches following phosphorylation by mTOR/Raptor. Free S6K1 is then able to phosphorylate a number of its targets, including eIF4B.^[5]

Interactions

P70-S6 Kinase 1 has been shown to interact with:

• COASY,^[6]
• CSNK2B,^[7]
• EIF3B,^[8]
• KIAA1303,^{[9][10][11][12]}
• MTOR,^{[13][14][15][16][17][18][19][20][21][22][23][24]}
• POLDIP3,^[25]
• PPP2R2A,^[26][27]
• RBX1,^[28] and
• UBC.^[28]

See also

• Ribosomal S6 kinase
• P70S6 kinase
• RPS6KA1

References

1. 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.
2. "Entrez Gene: RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1".
3. Carnevalli LS, Masuda K, Frigerio F, Le Bacquer O, Um SH, Gandin V, Topisirovic I, Sonenberg N, Thomas G, Kozma SC (May 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.
4. 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.
5. 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: 569–580. doi:10.1016/j.cell.2005.10.024. PMID 16286006. Retrieved 1 March 2016.
6. 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.
7. 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.
8. 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.
9. Ali SM, Sabatini DM (May 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.
10. 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.
11. 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.
12. Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K (May 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis PB, Thomas G (May 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. Panasyuk G, Nemazanyy I, Filonenko V, Gout I (May 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.