P70-S6 Kinase 1

This gene encodes a member of the S6K family of serine/threonine kinases, which phosphorylate 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.

The p70S6 kinase is a downstream target of mTOR (mammalian target of rapamycin) signaling, specifically mTORC1, an mTOR-containing complex characterized by the inclusion of Raptor rather than Rictor (mTORC2). mTOR can be activated via an AND-gate-like mechanism at the lysosome, integrating signals about growth factors and bioavailability of important molecules. For instance, amino acids such as arginine and leucine can trigger lysosomal recruitment of mTORC1. Once at the lysosome, mTOR can be activated by Rheb, a small, lysosomal-resident GTPase, in its GTP-bound state. Rheb GTPase activity is stimulated (and therefore capacity to activate mTOR diminished) by the upstream TSC complex, which is inhibited by IGF signalling. Thus, the AND gate consists of proper localization by sufficiency of amino acids and activation by growth factors. Once mTOR has been properly localized and activated, it can phosphorylate downstream targets such as p70S6K, 4EBP, and ULK1 which are important for regulating protein anabolic/catabolic balance.

Physical exercise activates protein synthesis via phosphorylation (activation) of p70S6K in a pathway that is dependent on mTOR, specifically mTORC1. This has been demonstrated by using an inhibitor of mTOR, rapamycin, to block an increase in muscle mass, despite increases in load (e.g., exercise). Exercise has been shown to increase levels of IGF-1 in muscle, thus inducing the IGF-1/PI3K/Akt/p70S6K signaling pathway, and thereby increasing the protein synthesis that is required to build muscle.

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.{{cite journal | vauthors = Carnevalli LS, Masuda K, Frigerio F, Le Bacquer O, Um SH, Gandin V, Topisirovic I, Sonenberg N, Thomas G, Kozma SC | title = S6K1 plays a critical role in early adipocyte differentiation | journal = Developmental Cell | volume = 18 | issue = 5 | pages = 763–774 | date = May 2010 | pmid = 20493810 | pmc = 2918254 | doi = 10.1016/j.devcel.2010.02.018 }}

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.{{cite journal | vauthors = Van Dyke JM, Bain JL, Riley DA | title = Stretch-activated signaling is modulated by stretch magnitude and contraction | journal = Muscle & Nerve | volume = 49 | issue = 1 | pages = 98–107 | date = January 2014 | pmid = 23620271 | doi = 10.1002/mus.23880 | s2cid = 206294774 }}

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.{{cite journal | vauthors = Holz MK, Ballif BA, Gygi SP, Blenis J | title = mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events | journal = Cell | volume = 123 | issue = 4 | pages = 569–580 | date = November 2005 | pmid = 16286006 | doi = 10.1016/j.cell.2005.10.024 | s2cid = 11118504 | doi-access = free }}

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

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• COASY,{{cite journal | vauthors = Nemazanyy I, Panasyuk G, Zhyvoloup A, Panayotou G, Gout IT, Filonenko V | title = Specific interaction between S6K1 and CoA synthase: a potential link between the mTOR/S6K pathway, CoA biosynthesis and energy metabolism | journal = FEBS Letters | volume = 578 | issue = 3 | pages = 357–362 | date = December 2004 | pmid = 15589845 | doi = 10.1016/j.febslet.2004.10.091 | s2cid = 9916948 | doi-access = free | bibcode = 2004FEBSL.578..357N }}
• CSNK2B,{{cite journal | vauthors = Panasyuk G, Nemazanyy I, Zhyvoloup A, Bretner M, Litchfield DW, Filonenko V, Gout IT | title = Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17 | journal = The Journal of Biological Chemistry | volume = 281 | issue = 42 | pages = 31188–31201 | date = October 2006 | pmid = 16895915 | doi = 10.1074/jbc.M602618200 | doi-access = free }}
• EIF3B,{{cite journal | vauthors = Holz MK, Ballif BA, Gygi SP, Blenis J | title = mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events | journal = Cell | volume = 123 | issue = 4 | pages = 569–580 | date = November 2005 | pmid = 16286006 | doi = 10.1016/j.cell.2005.10.024 | s2cid = 11118504 | doi-access = free }}
• KIAA1303,{{cite journal | vauthors = Ali SM, Sabatini DM | title = Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site | journal = The Journal of Biological Chemistry | volume = 280 | issue = 20 | pages = 19445–19448 | date = May 2005 | pmid = 15809305 | doi = 10.1074/jbc.C500125200 | doi-access = free }}{{cite journal | vauthors = Ha SH, Kim DH, Kim IS, Kim JH, Lee MN, Lee HJ, Kim JH, Jang SK, Suh PG, Ryu SH | title = PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals | journal = Cellular Signalling | volume = 18 | issue = 12 | pages = 2283–2291 | date = December 2006 | pmid = 16837165 | doi = 10.1016/j.cellsig.2006.05.021 }}{{cite journal | vauthors = Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K | title = Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action | journal = Cell | volume = 110 | issue = 2 | pages = 177–189 | date = July 2002 | pmid = 12150926 | doi = 10.1016/S0092-8674(02)00833-4 | s2cid = 6438316 | doi-access = free }}{{cite journal | vauthors = Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K | title = The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif | journal = The Journal of Biological Chemistry | volume = 278 | issue = 18 | pages = 15461–15464 | date = May 2003 | pmid = 12604610 | doi = 10.1074/jbc.C200665200 | doi-access = free }}
• MTOR,{{cite journal | vauthors = Chiang GG, Abraham RT | title = Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase | journal = The Journal of Biological Chemistry | volume = 280 | issue = 27 | pages = 25485–25490 | date = July 2005 | pmid = 15899889 | doi = 10.1074/jbc.M501707200 | doi-access = free }}{{cite journal | vauthors = Holz MK, Blenis J | title = Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase | journal = The Journal of Biological Chemistry | volume = 280 | issue = 28 | pages = 26089–26093 | date = July 2005 | pmid = 15905173 | doi = 10.1074/jbc.M504045200 | doi-access = free }}{{cite journal | vauthors = Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K | title = Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro | journal = The Journal of Biological Chemistry | volume = 274 | issue = 48 | pages = 34493–34498 | date = November 1999 | pmid = 10567431 | doi = 10.1074/jbc.274.48.34493 | hdl-access = free | doi-access = free | hdl = 20.500.14094/D1002182 }}{{cite journal | vauthors = Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J | title = Rheb binds and regulates the mTOR kinase | journal = Current Biology | volume = 15 | issue = 8 | pages = 702–713 | date = April 2005 | pmid = 15854902 | doi = 10.1016/j.cub.2005.02.053 | s2cid = 3078706 | doi-access = free | bibcode = 2005CBio...15..702L }}{{cite journal | vauthors = Toral-Barza L, Zhang WG, Lamison C, Larocque J, Gibbons J, Yu K | title = 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 | journal = Biochemical and Biophysical Research Communications | volume = 332 | issue = 1 | pages = 304–310 | date = June 2005 | pmid = 15896331 | doi = 10.1016/j.bbrc.2005.04.117 }}{{cite journal | vauthors = Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis PB, Thomas G | title = Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site | journal = The Journal of Biological Chemistry | volume = 277 | issue = 22 | pages = 20104–20112 | date = May 2002 | pmid = 11914378 | doi = 10.1074/jbc.M201745200 | doi-access = free }}{{cite journal | vauthors = Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM | title = mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery | journal = Cell | volume = 110 | issue = 2 | pages = 163–175 | date = July 2002 | pmid = 12150925 | doi = 10.1016/S0092-8674(02)00808-5 | s2cid = 4656930 | doi-access = free }}{{cite journal | vauthors = Edinger AL, Linardic CM, Chiang GG, Thompson CB, Abraham RT | title = Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells | journal = Cancer Research | volume = 63 | issue = 23 | pages = 8451–8460 | date = December 2003 | pmid = 14679009 }}{{cite journal | vauthors = Leone M, Crowell KJ, Chen J, Jung D, Chiang GG, Sareth S, Abraham RT, Pellecchia M | title = The FRB domain of mTOR: NMR solution structure and inhibitor design | journal = Biochemistry | volume = 45 | issue = 34 | pages = 10294–10302 | date = August 2006 | pmid = 16922504 | doi = 10.1021/bi060976+ }}{{cite journal | vauthors = Takahashi T, Hara K, Inoue H, Kawa Y, Tokunaga C, Hidayat S, Yoshino K, Kuroda Y, Yonezawa K | title = Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and in vitro | journal = Genes to Cells | volume = 5 | issue = 9 | pages = 765–775 | date = September 2000 | pmid = 10971657 | doi = 10.1046/j.1365-2443.2000.00365.x | s2cid = 39048740 | doi-access = }}{{cite journal | vauthors = Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM | title = RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 4 | pages = 1432–1437 | date = February 1998 | pmid = 9465032 | pmc = 19032 | doi = 10.1073/pnas.95.4.1432 | doi-access = free | bibcode = 1998PNAS...95.1432B }}{{cite journal | vauthors = Sarbassov DD, Sabatini DM | title = Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex | journal = The Journal of Biological Chemistry | volume = 280 | issue = 47 | pages = 39505–39509 | date = November 2005 | pmid = 16183647 | doi = 10.1074/jbc.M506096200 | doi-access = free }}
• POLDIP3,{{cite journal | vauthors = Richardson CJ, Bröenstrup M, Fingar DC, Jülich K, Ballif BA, Gygi S, Blenis J | title = SKAR is a specific target of S6 kinase 1 in cell growth control | journal = Current Biology | volume = 14 | issue = 17 | pages = 1540–1549 | date = September 2004 | pmid = 15341740 | doi = 10.1016/j.cub.2004.08.061 | s2cid = 12838409 | doi-access = free | bibcode = 2004CBio...14.1540R }}
• PPP2R2A,{{cite journal | vauthors = Peterson RT, Desai BN, Hardwick JS, Schreiber SL | title = Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 8 | pages = 4438–4442 | date = April 1999 | pmid = 10200280 | pmc = 16350 | doi = 10.1073/pnas.96.8.4438 | doi-access = free | bibcode = 1999PNAS...96.4438P }}{{cite journal | vauthors = Bishop JD, Nien WL, Dauphinee SM, Too CK | title = Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells | journal = The Journal of Endocrinology | volume = 190 | issue = 2 | pages = 307–312 | date = August 2006 | pmid = 16899564 | doi = 10.1677/joe.1.06368 | doi-access = free }}
• RBX1,{{cite journal | vauthors = Panasyuk G, Nemazanyy I, Filonenko V, Gout I | title = Ribosomal protein S6 kinase 1 interacts with and is ubiquitinated by ubiquitin ligase ROC1 | journal = Biochemical and Biophysical Research Communications | volume = 369 | issue = 2 | pages = 339–343 | date = May 2008 | pmid = 18279656 | doi = 10.1016/j.bbrc.2008.02.016 }} and
• UBC.

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• Ribosomal S6 kinase
• RPS6KA1

{{Reflist|2}}

• {{PDBe-KB2|P23443|Ribosomal protein S6 kinase beta-1}}

{{Serine/threonine-specific protein kinases}}

{{Enzymes}}

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Category:Protein kinases

Category:EC 2.7.11