Full text data of RPS6KB1
RPS6KB1
(STK14A)
[Confidence: low (only semi-automatic identification from reviews)]
Ribosomal protein S6 kinase beta-1; S6K-beta-1; S6K1; 2.7.11.1 (70 kDa ribosomal protein S6 kinase 1; P70S6K1; p70-S6K 1; Ribosomal protein S6 kinase I; Serine/threonine-protein kinase 14A; p70 ribosomal S6 kinase alpha; p70 S6 kinase alpha; p70 S6K-alpha; p70 S6KA)
Ribosomal protein S6 kinase beta-1; S6K-beta-1; S6K1; 2.7.11.1 (70 kDa ribosomal protein S6 kinase 1; P70S6K1; p70-S6K 1; Ribosomal protein S6 kinase I; Serine/threonine-protein kinase 14A; p70 ribosomal S6 kinase alpha; p70 S6 kinase alpha; p70 S6K-alpha; p70 S6KA)
UniProt
P23443
ID KS6B1_HUMAN Reviewed; 525 AA.
AC P23443;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-OCT-2004, sequence version 2.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Ribosomal protein S6 kinase beta-1;
DE Short=S6K-beta-1;
DE Short=S6K1;
DE EC=2.7.11.1;
DE AltName: Full=70 kDa ribosomal protein S6 kinase 1;
DE Short=P70S6K1;
DE Short=p70-S6K 1;
DE AltName: Full=Ribosomal protein S6 kinase I;
DE AltName: Full=Serine/threonine-protein kinase 14A;
DE AltName: Full=p70 ribosomal S6 kinase alpha;
DE Short=p70 S6 kinase alpha;
DE Short=p70 S6K-alpha;
DE Short=p70 S6KA;
GN Name=RPS6KB1; Synonyms=STK14A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE INITIATION.
RX PubMed=1922062;
RA Grove J., Bonerjee P., Balasubramanyam A., Coffer P., Price D.J.,
RA Avruch J., Woodgett J.R.;
RT "Cloning and expression of two human p70 S6 kinase polypeptides
RT differing only at their amino termini.";
RL Mol. Cell. Biol. 11:5541-5550(1991).
RN [2]
RP TISSUE SPECIFICITY.
RX PubMed=9804755; DOI=10.1074/jbc.273.46.30061;
RA Gout I., Minami T., Hara K., Tsujishita Y., Filonenko V.,
RA Waterfield M.D., Yonezawa K.;
RT "Molecular cloning and characterization of a novel p70 S6 kinase, p70
RT S6 kinase beta containing a proline-rich region.";
RL J. Biol. Chem. 273:30061-30064(1998).
RN [3]
RP ENZYME REGULATION, PHOSPHORYLATION AT THR-252, AND MUTAGENESIS OF
RP THR-412; SER-434; SER-441; THR-444 AND SER-447.
RX PubMed=9445476; DOI=10.1126/science.279.5351.707;
RA Pullen N., Dennis P.B., Andjelkovic M., Dufner A., Kozma S.C.,
RA Hemmings B.A., Thomas G.;
RT "Phosphorylation and activation of p70s6k by PDK1.";
RL Science 279:707-710(1998).
RN [4]
RP FUNCTION IN PHOSPHORYLATION OF EEF2K, AND FUNCTION IN TRANSLATION
RP REGULATION.
RX PubMed=11500364; DOI=10.1093/emboj/20.16.4370;
RA Wang X., Li W., Williams M., Terada N., Alessi D.R., Proud C.G.;
RT "Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6
RT kinase.";
RL EMBO J. 20:4370-4379(2001).
RN [5]
RP INTERACTION WITH RPTOR.
RX PubMed=12150926; DOI=10.1016/S0092-8674(02)00833-4;
RA Hara K., Maruki Y., Long X., Yoshino K., Oshiro N., Hidayat S.,
RA Tokunaga C., Avruch J., Yonezawa K.;
RT "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR
RT action.";
RL Cell 110:177-189(2002).
RN [6]
RP FUNCTION, AND INTERACTION WITH TRAF4.
RX PubMed=12801526; DOI=10.1016/S0145-2126(02)00325-9;
RA Fleckenstein D.S., Dirks W.G., Drexler H.G., Quentmeier H.;
RT "Tumor necrosis factor receptor-associated factor (TRAF) 4 is a new
RT binding partner for the p70S6 serine/threonine kinase.";
RL Leuk. Res. 27:687-694(2003).
RN [7]
RP FUNCTION, AND INTERACTION WITH POLDIP3.
RX PubMed=15341740; DOI=10.1016/j.cub.2004.08.061;
RA Richardson C.J., Broenstrup M., Fingar D.C., Julich K., Ballif B.A.,
RA Gygi S., Blenis J.;
RT "SKAR is a specific target of S6 kinase 1 in cell growth control.";
RL Curr. Biol. 14:1540-1549(2004).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF EIF4B.
RX PubMed=15071500; DOI=10.1038/sj.emboj.7600193;
RA Raught B., Peiretti F., Gingras A.C., Livingstone M., Shahbazian D.,
RA Mayeur G.L., Polakiewicz R.D., Sonenberg N., Hershey J.W.;
RT "Phosphorylation of eucaryotic translation initiation factor 4B Ser422
RT is modulated by S6 kinases.";
RL EMBO J. 23:1761-1769(2004).
RN [9]
RP FUNCTION IN CELL CYCLE PROGRESSION.
RX PubMed=14673156; DOI=10.1128/MCB.24.1.200-216.2004;
RA Fingar D.C., Richardson C.J., Tee A.R., Cheatham L., Tsou C.,
RA Blenis J.;
RT "mTOR controls cell cycle progression through its cell growth
RT effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor
RT 4E.";
RL Mol. Cell. Biol. 24:200-216(2004).
RN [10]
RP FUNCTION IN TRANSLATION INITIATION, INTERACTION WITH EIF3B AND EIF3C,
RP AND MUTAGENESIS OF THR-412.
RX PubMed=16286006; DOI=10.1016/j.cell.2005.10.024;
RA Holz M.K., Ballif B.A., Gygi S.P., Blenis J.;
RT "mTOR and S6K1 mediate assembly of the translation preinitiation
RT complex through dynamic protein interchange and ordered
RT phosphorylation events.";
RL Cell 123:569-580(2005).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF GSK3B.
RX PubMed=17052453; DOI=10.1016/j.molcel.2006.09.019;
RA Zhang H.H., Lipovsky A.I., Dibble C.C., Sahin M., Manning B.D.;
RT "S6K1 regulates GSK3 under conditions of mTOR-dependent feedback
RT inhibition of Akt.";
RL Mol. Cell 24:185-197(2006).
RN [12]
RP FUNCTION.
RX PubMed=17053147; DOI=10.1126/science.1130276;
RA Dorrello N.V., Peschiaroli A., Guardavaccaro D., Colburn N.H.,
RA Sherman N.E., Pagano M.;
RT "S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein
RT translation and cell growth.";
RL Science 314:467-471(2006).
RN [13]
RP ENZYME REGULATION, AND MUTAGENESIS OF LYS-167 AND SER-394.
RX PubMed=17446865; DOI=10.1038/sj.emboj.7601682;
RA Hauge C., Antal T.L., Hirschberg D., Doehn U., Thorup K.,
RA Idrissova L., Hansen K., Jensen O.N., Jorgensen T.J., Biondi R.M.,
RA Frodin M.;
RT "Mechanism for activation of the growth factor-activated AGC kinases
RT by turn motif phosphorylation.";
RL EMBO J. 26:2251-2261(2007).
RN [14]
RP FUNCTION IN PHOSPHORYLATION OF URI1, DEPHOSPHORYLATION AT THR-412 BY
RP PPP1CC, AND SUBCELLULAR LOCATION.
RX PubMed=17936702; DOI=10.1016/j.molcel.2007.08.010;
RA Djouder N., Metzler S.C., Schmidt A., Wirbelauer C., Gstaiger M.,
RA Aebersold R., Hess D., Krek W.;
RT "S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes
RT activates a negative feedback program that counters S6K1 survival
RT signaling.";
RL Mol. Cell 28:28-40(2007).
RN [15]
RP PHOSPHORYLATION AT THR-412.
RX PubMed=18925875; DOI=10.1042/BJ20081668;
RA Garcia-Martinez J.M., Alessi D.R.;
RT "mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation
RT and activation of serum- and glucocorticoid-induced protein kinase 1
RT (SGK1).";
RL Biochem. J. 416:375-385(2008).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF IRS1, FUNCTION IN GLUCOSE HOMEOSTASIS,
RP AND INTERACTION WITH IRS1.
RX PubMed=18952604; DOI=10.1074/jbc.M806480200;
RA Zhang J., Gao Z., Yin J., Quon M.J., Ye J.;
RT "S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin
RT resistance in response to TNF-(alpha) signaling through IKK2.";
RL J. Biol. Chem. 283:35375-35382(2008).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP FUNCTION, ALTERNATIVE SPLICING, PHOSPHORYLATION AT SER-394; THR-412;
RP THR-444 AND SER-447, AND SUBCELLULAR LOCATION.
RX PubMed=19085255; DOI=10.1080/08977190802556986;
RA Kim D., Akcakanat A., Singh G., Sharma C., Meric-Bernstam F.;
RT "Regulation and localization of ribosomal protein S6 kinase 1
RT isoforms.";
RL Growth Factors 27:12-21(2009).
RN [19]
RP ENZYME REGULATION, AND MUTAGENESIS OF THR-412.
RX PubMed=19570988; DOI=10.1074/jbc.M109.032177;
RA Keshwani M.M., Gao X., Harris T.K.;
RT "Mechanism of PDK1-catalyzed Thr-229 phosphorylation of the S6K1
RT protein kinase.";
RL J. Biol. Chem. 284:22611-22624(2009).
RN [20]
RP FUNCTION IN PHOSPHORYLATION OF RICTOR.
RX PubMed=19720745; DOI=10.1128/MCB.00735-09;
RA Dibble C.C., Asara J.M., Manning B.D.;
RT "Characterization of Rictor phosphorylation sites reveals direct
RT regulation of mTOR complex 2 by S6K1.";
RL Mol. Cell. Biol. 29:5657-5670(2009).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-447, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-304, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF RICTOR.
RX PubMed=19995915; DOI=10.1128/MCB.00601-09;
RA Julien L.A., Carriere A., Moreau J., Roux P.P.;
RT "mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and
RT regulates mTORC2 signaling.";
RL Mol. Cell. Biol. 30:908-921(2010).
RN [24]
RP FUNCTION IN PHOSPHORYLATION OF RICTOR.
RX PubMed=19935711; DOI=10.1038/onc.2009.401;
RA Treins C., Warne P.H., Magnuson M.A., Pende M., Downward J.;
RT "Rictor is a novel target of p70 S6 kinase-1.";
RL Oncogene 29:1003-1016(2010).
RN [25]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=18092230; DOI=10.1080/08977190701779101;
RA Jastrzebski K., Hannan K.M., Tchoubrieva E.B., Hannan R.D.,
RA Pearson R.B.;
RT "Coordinate regulation of ribosome biogenesis and function by the
RT ribosomal protein S6 kinase, a key mediator of mTOR function.";
RL Growth Factors 25:209-226(2007).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-441; THR-444; SER-447
RP AND SER-452, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [27]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=20932932; DOI=10.1016/j.biocel.2010.09.018;
RA Fenton T.R., Gout I.T.;
RT "Functions and regulation of the 70kDa ribosomal S6 kinases.";
RL Int. J. Biochem. Cell Biol. 43:47-59(2011).
RN [28]
RP FUNCTION, PHOSPHORYLATION OF CAD, AND PHOSPHORYLATION BY MTOR.
RX PubMed=23429703; DOI=10.1126/science.1228792;
RA Ben-Sahra I., Howell J.J., Asara J.M., Manning B.D.;
RT "Stimulation of de novo pyrimidine synthesis by growth signaling
RT through mTOR and S6K1.";
RL Science 339:1323-1328(2013).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 75-399, AND PHOSPHORYLATION
RP AT THR-252.
RX PubMed=19864428; DOI=10.1074/jbc.M109.040667;
RA Sunami T., Byrne N., Diehl R.E., Funabashi K., Hall D.L., Ikuta M.,
RA Patel S.B., Shipman J.M., Smith R.F., Takahashi I., Zugay-Murphy J.,
RA Iwasawa Y., Lumb K.J., Munshi S.K., Sharma S.;
RT "Structural basis of human p70 ribosomal S6 kinase-1 regulation by
RT activation loop phosphorylation.";
RL J. Biol. Chem. 285:4587-4594(2010).
RN [30]
RP VARIANT [LARGE SCALE ANALYSIS] GLU-289.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [31]
RP VARIANTS [LARGE SCALE ANALYSIS] ILE-225; CYS-272; CYS-276 AND ALA-398.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase that acts downstream of
CC mTOR signaling in response to growth factors and nutrients to
CC promote cell proliferation, cell growth and cell cycle
CC progression. Regulates protein synthesis through phosphorylation
CC of EIF4B, RPS6 and EEF2K, and contributes to cell survival by
CC repressing the pro-apoptotic function of BAD. Under conditions of
CC nutrient depletion, the inactive form associates with the EIF3
CC translation initiation complex. Upon mitogenic stimulation,
CC phosphorylation by the mammalian target of rapamycin complex 1
CC (mTORC1) leads to dissociation from the EIF3 complex and
CC activation. The active form then phosphorylates and activates
CC several substrates in the preinitiation complex, including the
CC EIF2B complex and the cap-binding complex component EIF4B. Also
CC controls translation initiation by phosphorylating a negative
CC regulator of EIF4A, PDCD4, targeting it for ubiquitination and
CC subsequent proteolysis. Promotes initiation of the pioneer round
CC of protein synthesis by phosphorylating POLDIP3/SKAR. In response
CC to IGF1, activates translation elongation by phosphorylating EEF2
CC kinase (EEF2K), which leads to its inhibition and thus activation
CC of EEF2. Also plays a role in feedback regulation of mTORC2 by
CC mTORC1 by phosphorylating RICTOR, resulting in the inhibition of
CC mTORC2 and AKT1 signaling. Mediates cell survival by
CC phosphorylating the pro-apoptotic protein BAD and suppressing its
CC pro-apoptotic function. Phosphorylates mitochondrial URI1 leading
CC to dissociation of a URI1-PPP1CC complex. The free mitochondrial
CC PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is
CC proposed to be a negative feedback mechanism for the RPS6KB1 anti-
CC apoptotic function. Mediates TNF-alpha-induced insulin resistance
CC by phosphorylating IRS1 at multiple serine residues, resulting in
CC accelerated degradation of IRS1. In cells lacking functional TSC1-
CC 2 complex, constitutively phosphorylates and inhibits GSK3B. May
CC be involved in cytoskeletal rearrangement through binding to
CC neurabin. Phosphorylates and activates the pyrimidine biosynthesis
CC enzyme CAD, downstream of MTOR.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Activation requires multiple phosphorylation
CC events on serine/threonine residues. Activation appears to be
CC first mediated by phosphorylation of multiple sites in the
CC autoinhibitory domain, which facilitates phosphorylation at Thr-
CC 412, disrupting the autoinhibitory mechanism and allowing
CC phosphorylation of Thr-252 by PDPK1. The active conformation of
CC the kinase is believed to be stabilized by a mechanism involving
CC three conserved phosphorylation sites located in the kinase domain
CC activation loop (Thr-252) and in the AGC-kinase C-terminal domain
CC (Ser-394 in the middle of the tail/linker region and Thr-412
CC within a hydrophobic motif at its end). Activated by mTORC1;
CC isoform Alpha I and isoform Alpha II are sensitive to rapamycin,
CC which inhibits activating phosphorylation at Thr-412. Activated by
CC PDPK1.
CC -!- SUBUNIT: Interacts with PPP1R9A/neurabin-1 (By similarity).
CC Interacts with RPTOR. Interacts with IRS1. Interacts with EIF3B
CC and EIF3C. Interacts with POLDIP3 and TRAF4.
CC -!- INTERACTION:
CC P08151:GLI1; NbExp=4; IntAct=EBI-1775921, EBI-308084;
CC Q00005:PPP2R2B; NbExp=2; IntAct=EBI-1775921, EBI-1052159;
CC -!- SUBCELLULAR LOCATION: Cell junction, synapse, synaptosome (By
CC similarity). Mitochondrion outer membrane. Mitochondrion.
CC Note=Colocalizes with URI1 at mitochondrion.
CC -!- SUBCELLULAR LOCATION: Isoform Alpha I: Nucleus. Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform Alpha II: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Comment=Additional isoforms seem to exist;
CC Name=Alpha I; Synonyms=p80-S6K 1;
CC IsoId=P23443-1; Sequence=Displayed;
CC Name=Alpha II;
CC IsoId=P23443-2; Sequence=VSP_018839;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DOMAIN: The autoinhibitory domain is believed to block
CC phosphorylation within the AGC-kinase C-terminal domain and the
CC activation loop.
CC -!- DOMAIN: The TOS (TOR signaling) motif is essential for activation
CC by mTORC1 (By similarity).
CC -!- PTM: Phosphorylation at Thr-412 is regulated by mTORC1. The
CC phosphorylation at this site is maintained by an agonist-dependent
CC autophosphorylation mechanism (By similarity). Activated by
CC phosphorylation at Thr-252 by PDPK1. Dephosphorylation by PPP1CC
CC at Thr-412 in mitochondrion.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. S6 kinase subfamily.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
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DR EMBL; M60724; AAA36410.1; -; mRNA.
DR EMBL; M60725; AAA36411.1; -; mRNA.
DR PIR; A41687; A41687.
DR RefSeq; NP_001258989.1; NM_001272060.1.
DR RefSeq; NP_003152.1; NM_003161.3.
DR UniGene; Hs.463642; -.
DR PDB; 3A60; X-ray; 2.80 A; A/B=75-399.
DR PDB; 3A61; X-ray; 3.43 A; A=75-399.
DR PDB; 3A62; X-ray; 2.35 A; A=75-399.
DR PDB; 4L3J; X-ray; 2.10 A; A=75-375.
DR PDB; 4L3L; X-ray; 2.10 A; A=75-375.
DR PDB; 4L42; X-ray; 2.80 A; A=75-404.
DR PDB; 4L43; X-ray; 3.00 A; A=75-417.
DR PDB; 4L44; X-ray; 2.90 A; A=75-417.
DR PDB; 4L45; X-ray; 2.90 A; A=75-417.
DR PDB; 4L46; X-ray; 3.01 A; A=75-417.
DR PDBsum; 3A60; -.
DR PDBsum; 3A61; -.
DR PDBsum; 3A62; -.
DR PDBsum; 4L3J; -.
DR PDBsum; 4L3L; -.
DR PDBsum; 4L42; -.
DR PDBsum; 4L43; -.
DR PDBsum; 4L44; -.
DR PDBsum; 4L45; -.
DR PDBsum; 4L46; -.
DR ProteinModelPortal; P23443; -.
DR SMR; P23443; 56-421.
DR DIP; DIP-29986N; -.
DR IntAct; P23443; 19.
DR MINT; MINT-203709; -.
DR STRING; 9606.ENSP00000225577; -.
DR BindingDB; P23443; -.
DR ChEMBL; CHEMBL2111330; -.
DR GuidetoPHARMACOLOGY; 1525; -.
DR PhosphoSite; P23443; -.
DR DMDM; 54041234; -.
DR PaxDb; P23443; -.
DR PRIDE; P23443; -.
DR DNASU; 6198; -.
DR Ensembl; ENST00000225577; ENSP00000225577; ENSG00000108443.
DR GeneID; 6198; -.
DR KEGG; hsa:6198; -.
DR UCSC; uc002ixy.4; human.
DR CTD; 6198; -.
DR GeneCards; GC17P057970; -.
DR HGNC; HGNC:10436; RPS6KB1.
DR HPA; CAB003838; -.
DR HPA; CAB018346; -.
DR MIM; 608938; gene.
DR neXtProt; NX_P23443; -.
DR PharmGKB; PA34851; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233033; -.
DR HOVERGEN; HBG108317; -.
DR InParanoid; P23443; -.
DR KO; K04688; -.
DR OMA; ANRMPAR; -.
DR PhylomeDB; P23443; -.
DR BRENDA; 2.7.11.1; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; P23443; -.
DR ChiTaRS; RPS6KB1; human.
DR EvolutionaryTrace; P23443; -.
DR GeneWiki; P70-S6_Kinase_1; -.
DR GenomeRNAi; 6198; -.
DR NextBio; 24073; -.
DR PRO; PR:P23443; -.
DR ArrayExpress; P23443; -.
DR Bgee; P23443; -.
DR CleanEx; HS_RPS6KB1; -.
DR Genevestigator; P23443; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0043005; C:neuron projection; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-KW.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042277; F:peptide binding; IEA:Ensembl.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0004711; F:ribosomal protein S6 kinase activity; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0016477; P:cell migration; IEA:Ensembl.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0007281; P:germ cell development; IEA:Ensembl.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007616; P:long-term memory; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:UniProtKB.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0048633; P:positive regulation of skeletal muscle tissue growth; IEA:Ensembl.
DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IEA:Ensembl.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0045948; P:positive regulation of translational initiation; IMP:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling cascade; IEA:Ensembl.
DR GO; GO:0046324; P:regulation of glucose import; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0014878; P:response to electrical stimulus involved in regulation of muscle adaptation; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0033762; P:response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0009408; P:response to heat; IEA:Ensembl.
DR GO; GO:0043201; P:response to leucine; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0033574; P:response to testosterone stimulus; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR GO; GO:0034612; P:response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0009611; P:response to wounding; IEA:Ensembl.
DR GO; GO:0014732; P:skeletal muscle atrophy; IEA:Ensembl.
DR GO; GO:0003009; P:skeletal muscle contraction; IEA:Ensembl.
DR GO; GO:0031929; P:TOR signaling cascade; IDA:UniProtKB.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR017892; Pkinase_C.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR016238; Ribosomal_S6_kinase.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00433; Pkinase_C; 1.
DR PIRSF; PIRSF000605; Ribsml_S6_kin_1; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative initiation; Apoptosis;
KW ATP-binding; Cell cycle; Cell junction; Complete proteome; Cytoplasm;
KW Kinase; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Serine/threonine-protein kinase; Synapse;
KW Synaptosome; Transferase; Translation regulation.
FT CHAIN 1 525 Ribosomal protein S6 kinase beta-1.
FT /FTId=PRO_0000024342.
FT DOMAIN 91 352 Protein kinase.
FT DOMAIN 353 423 AGC-kinase C-terminal.
FT NP_BIND 97 105 ATP (By similarity).
FT REGION 424 525 Autoinhibitory domain.
FT MOTIF 28 32 TOS motif.
FT ACT_SITE 218 218 Proton acceptor (By similarity).
FT BINDING 123 123 ATP (By similarity).
FT MOD_RES 252 252 Phosphothreonine; by PDPK1.
FT MOD_RES 304 304 N6-acetyllysine.
FT MOD_RES 394 394 Phosphoserine.
FT MOD_RES 412 412 Phosphothreonine; by MTOR, NEK6 and NEK7
FT (By similarity).
FT MOD_RES 434 434 Phosphoserine (By similarity).
FT MOD_RES 441 441 Phosphoserine.
FT MOD_RES 444 444 Phosphothreonine.
FT MOD_RES 447 447 Phosphoserine.
FT MOD_RES 452 452 Phosphoserine.
FT MOD_RES 516 516 N6-acetyllysine (By similarity).
FT VAR_SEQ 1 23 Missing (in isoform Alpha II).
FT /FTId=VSP_018839.
FT VARIANT 225 225 M -> I.
FT /FTId=VAR_040639.
FT VARIANT 272 272 R -> C.
FT /FTId=VAR_040640.
FT VARIANT 276 276 W -> C.
FT /FTId=VAR_040641.
FT VARIANT 289 289 G -> E (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035628.
FT VARIANT 398 398 S -> A.
FT /FTId=VAR_040642.
FT MUTAGEN 167 167 K->N: Greatly reduces activity. Greatly
FT reduces phosphorylation at T-412 and
FT moderately reduces phosphorylation at T-
FT 252.
FT MUTAGEN 394 394 S->A: Loss of activity. Loss of
FT phosphorylation at T-412.
FT MUTAGEN 412 412 T->E: Mimics phosphorylation. Facilitates
FT phosphorylation of T-252 by PDPK1; when
FT associated with E-434; E-441; E-444 and
FT E-447. Mimics phosphorylation. No effect
FT on interaction with PDPK1 and
FT phosphorylation of T-252. Impairs
FT association with the eIF3 complex.
FT MUTAGEN 434 434 S->E: Facilitates phosphorylation of T-
FT 252 by PDPK1; when associated with E-412;
FT E-441; E-444 and E-447.
FT MUTAGEN 441 441 S->E: Facilitates phosphorylation of T-
FT 252 by PDPK1; when associated with E-412;
FT E-434; E-444 and E-447.
FT MUTAGEN 444 444 T->E: Facilitates phosphorylation of T-
FT 252 by PDPK1; when associated with E-412;
FT E-434; E-441 and E-447.
FT MUTAGEN 447 447 S->E: Facilitates phosphorylation of T-
FT 252 by PDPK1; when associated with E-412;
FT E-434; E-441 and E-444.
FT HELIX 88 90
FT STRAND 91 99
FT STRAND 101 110
FT TURN 114 117
FT STRAND 119 127
FT TURN 128 132
FT HELIX 134 149
FT STRAND 158 163
FT STRAND 165 173
FT HELIX 180 187
FT HELIX 192 211
FT HELIX 221 223
FT STRAND 224 226
FT STRAND 232 234
FT STRAND 246 249
FT HELIX 262 266
FT HELIX 273 288
FT HELIX 298 307
FT STRAND 314 316
FT HELIX 318 327
FT HELIX 332 334
FT TURN 340 342
FT HELIX 343 347
FT HELIX 350 352
FT HELIX 357 361
FT HELIX 371 373
FT STRAND 374 377
FT TURN 380 382
FT HELIX 409 411
FT STRAND 413 415
SQ SEQUENCE 525 AA; 59140 MW; 2C3BA13CCDAF4AB3 CRC64;
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
//
ID KS6B1_HUMAN Reviewed; 525 AA.
AC P23443;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-OCT-2004, sequence version 2.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Ribosomal protein S6 kinase beta-1;
DE Short=S6K-beta-1;
DE Short=S6K1;
DE EC=2.7.11.1;
DE AltName: Full=70 kDa ribosomal protein S6 kinase 1;
DE Short=P70S6K1;
DE Short=p70-S6K 1;
DE AltName: Full=Ribosomal protein S6 kinase I;
DE AltName: Full=Serine/threonine-protein kinase 14A;
DE AltName: Full=p70 ribosomal S6 kinase alpha;
DE Short=p70 S6 kinase alpha;
DE Short=p70 S6K-alpha;
DE Short=p70 S6KA;
GN Name=RPS6KB1; Synonyms=STK14A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE INITIATION.
RX PubMed=1922062;
RA Grove J., Bonerjee P., Balasubramanyam A., Coffer P., Price D.J.,
RA Avruch J., Woodgett J.R.;
RT "Cloning and expression of two human p70 S6 kinase polypeptides
RT differing only at their amino termini.";
RL Mol. Cell. Biol. 11:5541-5550(1991).
RN [2]
RP TISSUE SPECIFICITY.
RX PubMed=9804755; DOI=10.1074/jbc.273.46.30061;
RA Gout I., Minami T., Hara K., Tsujishita Y., Filonenko V.,
RA Waterfield M.D., Yonezawa K.;
RT "Molecular cloning and characterization of a novel p70 S6 kinase, p70
RT S6 kinase beta containing a proline-rich region.";
RL J. Biol. Chem. 273:30061-30064(1998).
RN [3]
RP ENZYME REGULATION, PHOSPHORYLATION AT THR-252, AND MUTAGENESIS OF
RP THR-412; SER-434; SER-441; THR-444 AND SER-447.
RX PubMed=9445476; DOI=10.1126/science.279.5351.707;
RA Pullen N., Dennis P.B., Andjelkovic M., Dufner A., Kozma S.C.,
RA Hemmings B.A., Thomas G.;
RT "Phosphorylation and activation of p70s6k by PDK1.";
RL Science 279:707-710(1998).
RN [4]
RP FUNCTION IN PHOSPHORYLATION OF EEF2K, AND FUNCTION IN TRANSLATION
RP REGULATION.
RX PubMed=11500364; DOI=10.1093/emboj/20.16.4370;
RA Wang X., Li W., Williams M., Terada N., Alessi D.R., Proud C.G.;
RT "Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6
RT kinase.";
RL EMBO J. 20:4370-4379(2001).
RN [5]
RP INTERACTION WITH RPTOR.
RX PubMed=12150926; DOI=10.1016/S0092-8674(02)00833-4;
RA Hara K., Maruki Y., Long X., Yoshino K., Oshiro N., Hidayat S.,
RA Tokunaga C., Avruch J., Yonezawa K.;
RT "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR
RT action.";
RL Cell 110:177-189(2002).
RN [6]
RP FUNCTION, AND INTERACTION WITH TRAF4.
RX PubMed=12801526; DOI=10.1016/S0145-2126(02)00325-9;
RA Fleckenstein D.S., Dirks W.G., Drexler H.G., Quentmeier H.;
RT "Tumor necrosis factor receptor-associated factor (TRAF) 4 is a new
RT binding partner for the p70S6 serine/threonine kinase.";
RL Leuk. Res. 27:687-694(2003).
RN [7]
RP FUNCTION, AND INTERACTION WITH POLDIP3.
RX PubMed=15341740; DOI=10.1016/j.cub.2004.08.061;
RA Richardson C.J., Broenstrup M., Fingar D.C., Julich K., Ballif B.A.,
RA Gygi S., Blenis J.;
RT "SKAR is a specific target of S6 kinase 1 in cell growth control.";
RL Curr. Biol. 14:1540-1549(2004).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF EIF4B.
RX PubMed=15071500; DOI=10.1038/sj.emboj.7600193;
RA Raught B., Peiretti F., Gingras A.C., Livingstone M., Shahbazian D.,
RA Mayeur G.L., Polakiewicz R.D., Sonenberg N., Hershey J.W.;
RT "Phosphorylation of eucaryotic translation initiation factor 4B Ser422
RT is modulated by S6 kinases.";
RL EMBO J. 23:1761-1769(2004).
RN [9]
RP FUNCTION IN CELL CYCLE PROGRESSION.
RX PubMed=14673156; DOI=10.1128/MCB.24.1.200-216.2004;
RA Fingar D.C., Richardson C.J., Tee A.R., Cheatham L., Tsou C.,
RA Blenis J.;
RT "mTOR controls cell cycle progression through its cell growth
RT effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor
RT 4E.";
RL Mol. Cell. Biol. 24:200-216(2004).
RN [10]
RP FUNCTION IN TRANSLATION INITIATION, INTERACTION WITH EIF3B AND EIF3C,
RP AND MUTAGENESIS OF THR-412.
RX PubMed=16286006; DOI=10.1016/j.cell.2005.10.024;
RA Holz M.K., Ballif B.A., Gygi S.P., Blenis J.;
RT "mTOR and S6K1 mediate assembly of the translation preinitiation
RT complex through dynamic protein interchange and ordered
RT phosphorylation events.";
RL Cell 123:569-580(2005).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF GSK3B.
RX PubMed=17052453; DOI=10.1016/j.molcel.2006.09.019;
RA Zhang H.H., Lipovsky A.I., Dibble C.C., Sahin M., Manning B.D.;
RT "S6K1 regulates GSK3 under conditions of mTOR-dependent feedback
RT inhibition of Akt.";
RL Mol. Cell 24:185-197(2006).
RN [12]
RP FUNCTION.
RX PubMed=17053147; DOI=10.1126/science.1130276;
RA Dorrello N.V., Peschiaroli A., Guardavaccaro D., Colburn N.H.,
RA Sherman N.E., Pagano M.;
RT "S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein
RT translation and cell growth.";
RL Science 314:467-471(2006).
RN [13]
RP ENZYME REGULATION, AND MUTAGENESIS OF LYS-167 AND SER-394.
RX PubMed=17446865; DOI=10.1038/sj.emboj.7601682;
RA Hauge C., Antal T.L., Hirschberg D., Doehn U., Thorup K.,
RA Idrissova L., Hansen K., Jensen O.N., Jorgensen T.J., Biondi R.M.,
RA Frodin M.;
RT "Mechanism for activation of the growth factor-activated AGC kinases
RT by turn motif phosphorylation.";
RL EMBO J. 26:2251-2261(2007).
RN [14]
RP FUNCTION IN PHOSPHORYLATION OF URI1, DEPHOSPHORYLATION AT THR-412 BY
RP PPP1CC, AND SUBCELLULAR LOCATION.
RX PubMed=17936702; DOI=10.1016/j.molcel.2007.08.010;
RA Djouder N., Metzler S.C., Schmidt A., Wirbelauer C., Gstaiger M.,
RA Aebersold R., Hess D., Krek W.;
RT "S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes
RT activates a negative feedback program that counters S6K1 survival
RT signaling.";
RL Mol. Cell 28:28-40(2007).
RN [15]
RP PHOSPHORYLATION AT THR-412.
RX PubMed=18925875; DOI=10.1042/BJ20081668;
RA Garcia-Martinez J.M., Alessi D.R.;
RT "mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation
RT and activation of serum- and glucocorticoid-induced protein kinase 1
RT (SGK1).";
RL Biochem. J. 416:375-385(2008).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF IRS1, FUNCTION IN GLUCOSE HOMEOSTASIS,
RP AND INTERACTION WITH IRS1.
RX PubMed=18952604; DOI=10.1074/jbc.M806480200;
RA Zhang J., Gao Z., Yin J., Quon M.J., Ye J.;
RT "S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin
RT resistance in response to TNF-(alpha) signaling through IKK2.";
RL J. Biol. Chem. 283:35375-35382(2008).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP FUNCTION, ALTERNATIVE SPLICING, PHOSPHORYLATION AT SER-394; THR-412;
RP THR-444 AND SER-447, AND SUBCELLULAR LOCATION.
RX PubMed=19085255; DOI=10.1080/08977190802556986;
RA Kim D., Akcakanat A., Singh G., Sharma C., Meric-Bernstam F.;
RT "Regulation and localization of ribosomal protein S6 kinase 1
RT isoforms.";
RL Growth Factors 27:12-21(2009).
RN [19]
RP ENZYME REGULATION, AND MUTAGENESIS OF THR-412.
RX PubMed=19570988; DOI=10.1074/jbc.M109.032177;
RA Keshwani M.M., Gao X., Harris T.K.;
RT "Mechanism of PDK1-catalyzed Thr-229 phosphorylation of the S6K1
RT protein kinase.";
RL J. Biol. Chem. 284:22611-22624(2009).
RN [20]
RP FUNCTION IN PHOSPHORYLATION OF RICTOR.
RX PubMed=19720745; DOI=10.1128/MCB.00735-09;
RA Dibble C.C., Asara J.M., Manning B.D.;
RT "Characterization of Rictor phosphorylation sites reveals direct
RT regulation of mTOR complex 2 by S6K1.";
RL Mol. Cell. Biol. 29:5657-5670(2009).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-447, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-304, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF RICTOR.
RX PubMed=19995915; DOI=10.1128/MCB.00601-09;
RA Julien L.A., Carriere A., Moreau J., Roux P.P.;
RT "mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and
RT regulates mTORC2 signaling.";
RL Mol. Cell. Biol. 30:908-921(2010).
RN [24]
RP FUNCTION IN PHOSPHORYLATION OF RICTOR.
RX PubMed=19935711; DOI=10.1038/onc.2009.401;
RA Treins C., Warne P.H., Magnuson M.A., Pende M., Downward J.;
RT "Rictor is a novel target of p70 S6 kinase-1.";
RL Oncogene 29:1003-1016(2010).
RN [25]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=18092230; DOI=10.1080/08977190701779101;
RA Jastrzebski K., Hannan K.M., Tchoubrieva E.B., Hannan R.D.,
RA Pearson R.B.;
RT "Coordinate regulation of ribosome biogenesis and function by the
RT ribosomal protein S6 kinase, a key mediator of mTOR function.";
RL Growth Factors 25:209-226(2007).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-441; THR-444; SER-447
RP AND SER-452, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [27]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=20932932; DOI=10.1016/j.biocel.2010.09.018;
RA Fenton T.R., Gout I.T.;
RT "Functions and regulation of the 70kDa ribosomal S6 kinases.";
RL Int. J. Biochem. Cell Biol. 43:47-59(2011).
RN [28]
RP FUNCTION, PHOSPHORYLATION OF CAD, AND PHOSPHORYLATION BY MTOR.
RX PubMed=23429703; DOI=10.1126/science.1228792;
RA Ben-Sahra I., Howell J.J., Asara J.M., Manning B.D.;
RT "Stimulation of de novo pyrimidine synthesis by growth signaling
RT through mTOR and S6K1.";
RL Science 339:1323-1328(2013).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 75-399, AND PHOSPHORYLATION
RP AT THR-252.
RX PubMed=19864428; DOI=10.1074/jbc.M109.040667;
RA Sunami T., Byrne N., Diehl R.E., Funabashi K., Hall D.L., Ikuta M.,
RA Patel S.B., Shipman J.M., Smith R.F., Takahashi I., Zugay-Murphy J.,
RA Iwasawa Y., Lumb K.J., Munshi S.K., Sharma S.;
RT "Structural basis of human p70 ribosomal S6 kinase-1 regulation by
RT activation loop phosphorylation.";
RL J. Biol. Chem. 285:4587-4594(2010).
RN [30]
RP VARIANT [LARGE SCALE ANALYSIS] GLU-289.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [31]
RP VARIANTS [LARGE SCALE ANALYSIS] ILE-225; CYS-272; CYS-276 AND ALA-398.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase that acts downstream of
CC mTOR signaling in response to growth factors and nutrients to
CC promote cell proliferation, cell growth and cell cycle
CC progression. Regulates protein synthesis through phosphorylation
CC of EIF4B, RPS6 and EEF2K, and contributes to cell survival by
CC repressing the pro-apoptotic function of BAD. Under conditions of
CC nutrient depletion, the inactive form associates with the EIF3
CC translation initiation complex. Upon mitogenic stimulation,
CC phosphorylation by the mammalian target of rapamycin complex 1
CC (mTORC1) leads to dissociation from the EIF3 complex and
CC activation. The active form then phosphorylates and activates
CC several substrates in the preinitiation complex, including the
CC EIF2B complex and the cap-binding complex component EIF4B. Also
CC controls translation initiation by phosphorylating a negative
CC regulator of EIF4A, PDCD4, targeting it for ubiquitination and
CC subsequent proteolysis. Promotes initiation of the pioneer round
CC of protein synthesis by phosphorylating POLDIP3/SKAR. In response
CC to IGF1, activates translation elongation by phosphorylating EEF2
CC kinase (EEF2K), which leads to its inhibition and thus activation
CC of EEF2. Also plays a role in feedback regulation of mTORC2 by
CC mTORC1 by phosphorylating RICTOR, resulting in the inhibition of
CC mTORC2 and AKT1 signaling. Mediates cell survival by
CC phosphorylating the pro-apoptotic protein BAD and suppressing its
CC pro-apoptotic function. Phosphorylates mitochondrial URI1 leading
CC to dissociation of a URI1-PPP1CC complex. The free mitochondrial
CC PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is
CC proposed to be a negative feedback mechanism for the RPS6KB1 anti-
CC apoptotic function. Mediates TNF-alpha-induced insulin resistance
CC by phosphorylating IRS1 at multiple serine residues, resulting in
CC accelerated degradation of IRS1. In cells lacking functional TSC1-
CC 2 complex, constitutively phosphorylates and inhibits GSK3B. May
CC be involved in cytoskeletal rearrangement through binding to
CC neurabin. Phosphorylates and activates the pyrimidine biosynthesis
CC enzyme CAD, downstream of MTOR.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Activation requires multiple phosphorylation
CC events on serine/threonine residues. Activation appears to be
CC first mediated by phosphorylation of multiple sites in the
CC autoinhibitory domain, which facilitates phosphorylation at Thr-
CC 412, disrupting the autoinhibitory mechanism and allowing
CC phosphorylation of Thr-252 by PDPK1. The active conformation of
CC the kinase is believed to be stabilized by a mechanism involving
CC three conserved phosphorylation sites located in the kinase domain
CC activation loop (Thr-252) and in the AGC-kinase C-terminal domain
CC (Ser-394 in the middle of the tail/linker region and Thr-412
CC within a hydrophobic motif at its end). Activated by mTORC1;
CC isoform Alpha I and isoform Alpha II are sensitive to rapamycin,
CC which inhibits activating phosphorylation at Thr-412. Activated by
CC PDPK1.
CC -!- SUBUNIT: Interacts with PPP1R9A/neurabin-1 (By similarity).
CC Interacts with RPTOR. Interacts with IRS1. Interacts with EIF3B
CC and EIF3C. Interacts with POLDIP3 and TRAF4.
CC -!- INTERACTION:
CC P08151:GLI1; NbExp=4; IntAct=EBI-1775921, EBI-308084;
CC Q00005:PPP2R2B; NbExp=2; IntAct=EBI-1775921, EBI-1052159;
CC -!- SUBCELLULAR LOCATION: Cell junction, synapse, synaptosome (By
CC similarity). Mitochondrion outer membrane. Mitochondrion.
CC Note=Colocalizes with URI1 at mitochondrion.
CC -!- SUBCELLULAR LOCATION: Isoform Alpha I: Nucleus. Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform Alpha II: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Comment=Additional isoforms seem to exist;
CC Name=Alpha I; Synonyms=p80-S6K 1;
CC IsoId=P23443-1; Sequence=Displayed;
CC Name=Alpha II;
CC IsoId=P23443-2; Sequence=VSP_018839;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DOMAIN: The autoinhibitory domain is believed to block
CC phosphorylation within the AGC-kinase C-terminal domain and the
CC activation loop.
CC -!- DOMAIN: The TOS (TOR signaling) motif is essential for activation
CC by mTORC1 (By similarity).
CC -!- PTM: Phosphorylation at Thr-412 is regulated by mTORC1. The
CC phosphorylation at this site is maintained by an agonist-dependent
CC autophosphorylation mechanism (By similarity). Activated by
CC phosphorylation at Thr-252 by PDPK1. Dephosphorylation by PPP1CC
CC at Thr-412 in mitochondrion.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. S6 kinase subfamily.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
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DR EMBL; M60724; AAA36410.1; -; mRNA.
DR EMBL; M60725; AAA36411.1; -; mRNA.
DR PIR; A41687; A41687.
DR RefSeq; NP_001258989.1; NM_001272060.1.
DR RefSeq; NP_003152.1; NM_003161.3.
DR UniGene; Hs.463642; -.
DR PDB; 3A60; X-ray; 2.80 A; A/B=75-399.
DR PDB; 3A61; X-ray; 3.43 A; A=75-399.
DR PDB; 3A62; X-ray; 2.35 A; A=75-399.
DR PDB; 4L3J; X-ray; 2.10 A; A=75-375.
DR PDB; 4L3L; X-ray; 2.10 A; A=75-375.
DR PDB; 4L42; X-ray; 2.80 A; A=75-404.
DR PDB; 4L43; X-ray; 3.00 A; A=75-417.
DR PDB; 4L44; X-ray; 2.90 A; A=75-417.
DR PDB; 4L45; X-ray; 2.90 A; A=75-417.
DR PDB; 4L46; X-ray; 3.01 A; A=75-417.
DR PDBsum; 3A60; -.
DR PDBsum; 3A61; -.
DR PDBsum; 3A62; -.
DR PDBsum; 4L3J; -.
DR PDBsum; 4L3L; -.
DR PDBsum; 4L42; -.
DR PDBsum; 4L43; -.
DR PDBsum; 4L44; -.
DR PDBsum; 4L45; -.
DR PDBsum; 4L46; -.
DR ProteinModelPortal; P23443; -.
DR SMR; P23443; 56-421.
DR DIP; DIP-29986N; -.
DR IntAct; P23443; 19.
DR MINT; MINT-203709; -.
DR STRING; 9606.ENSP00000225577; -.
DR BindingDB; P23443; -.
DR ChEMBL; CHEMBL2111330; -.
DR GuidetoPHARMACOLOGY; 1525; -.
DR PhosphoSite; P23443; -.
DR DMDM; 54041234; -.
DR PaxDb; P23443; -.
DR PRIDE; P23443; -.
DR DNASU; 6198; -.
DR Ensembl; ENST00000225577; ENSP00000225577; ENSG00000108443.
DR GeneID; 6198; -.
DR KEGG; hsa:6198; -.
DR UCSC; uc002ixy.4; human.
DR CTD; 6198; -.
DR GeneCards; GC17P057970; -.
DR HGNC; HGNC:10436; RPS6KB1.
DR HPA; CAB003838; -.
DR HPA; CAB018346; -.
DR MIM; 608938; gene.
DR neXtProt; NX_P23443; -.
DR PharmGKB; PA34851; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233033; -.
DR HOVERGEN; HBG108317; -.
DR InParanoid; P23443; -.
DR KO; K04688; -.
DR OMA; ANRMPAR; -.
DR PhylomeDB; P23443; -.
DR BRENDA; 2.7.11.1; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; P23443; -.
DR ChiTaRS; RPS6KB1; human.
DR EvolutionaryTrace; P23443; -.
DR GeneWiki; P70-S6_Kinase_1; -.
DR GenomeRNAi; 6198; -.
DR NextBio; 24073; -.
DR PRO; PR:P23443; -.
DR ArrayExpress; P23443; -.
DR Bgee; P23443; -.
DR CleanEx; HS_RPS6KB1; -.
DR Genevestigator; P23443; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0043005; C:neuron projection; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-KW.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042277; F:peptide binding; IEA:Ensembl.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0004711; F:ribosomal protein S6 kinase activity; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0016477; P:cell migration; IEA:Ensembl.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0007281; P:germ cell development; IEA:Ensembl.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007616; P:long-term memory; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:UniProtKB.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0048633; P:positive regulation of skeletal muscle tissue growth; IEA:Ensembl.
DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IEA:Ensembl.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0045948; P:positive regulation of translational initiation; IMP:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling cascade; IEA:Ensembl.
DR GO; GO:0046324; P:regulation of glucose import; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0014878; P:response to electrical stimulus involved in regulation of muscle adaptation; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0033762; P:response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0009408; P:response to heat; IEA:Ensembl.
DR GO; GO:0043201; P:response to leucine; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0033574; P:response to testosterone stimulus; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR GO; GO:0034612; P:response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0009611; P:response to wounding; IEA:Ensembl.
DR GO; GO:0014732; P:skeletal muscle atrophy; IEA:Ensembl.
DR GO; GO:0003009; P:skeletal muscle contraction; IEA:Ensembl.
DR GO; GO:0031929; P:TOR signaling cascade; IDA:UniProtKB.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR017892; Pkinase_C.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR016238; Ribosomal_S6_kinase.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00433; Pkinase_C; 1.
DR PIRSF; PIRSF000605; Ribsml_S6_kin_1; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative initiation; Apoptosis;
KW ATP-binding; Cell cycle; Cell junction; Complete proteome; Cytoplasm;
KW Kinase; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Serine/threonine-protein kinase; Synapse;
KW Synaptosome; Transferase; Translation regulation.
FT CHAIN 1 525 Ribosomal protein S6 kinase beta-1.
FT /FTId=PRO_0000024342.
FT DOMAIN 91 352 Protein kinase.
FT DOMAIN 353 423 AGC-kinase C-terminal.
FT NP_BIND 97 105 ATP (By similarity).
FT REGION 424 525 Autoinhibitory domain.
FT MOTIF 28 32 TOS motif.
FT ACT_SITE 218 218 Proton acceptor (By similarity).
FT BINDING 123 123 ATP (By similarity).
FT MOD_RES 252 252 Phosphothreonine; by PDPK1.
FT MOD_RES 304 304 N6-acetyllysine.
FT MOD_RES 394 394 Phosphoserine.
FT MOD_RES 412 412 Phosphothreonine; by MTOR, NEK6 and NEK7
FT (By similarity).
FT MOD_RES 434 434 Phosphoserine (By similarity).
FT MOD_RES 441 441 Phosphoserine.
FT MOD_RES 444 444 Phosphothreonine.
FT MOD_RES 447 447 Phosphoserine.
FT MOD_RES 452 452 Phosphoserine.
FT MOD_RES 516 516 N6-acetyllysine (By similarity).
FT VAR_SEQ 1 23 Missing (in isoform Alpha II).
FT /FTId=VSP_018839.
FT VARIANT 225 225 M -> I.
FT /FTId=VAR_040639.
FT VARIANT 272 272 R -> C.
FT /FTId=VAR_040640.
FT VARIANT 276 276 W -> C.
FT /FTId=VAR_040641.
FT VARIANT 289 289 G -> E (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035628.
FT VARIANT 398 398 S -> A.
FT /FTId=VAR_040642.
FT MUTAGEN 167 167 K->N: Greatly reduces activity. Greatly
FT reduces phosphorylation at T-412 and
FT moderately reduces phosphorylation at T-
FT 252.
FT MUTAGEN 394 394 S->A: Loss of activity. Loss of
FT phosphorylation at T-412.
FT MUTAGEN 412 412 T->E: Mimics phosphorylation. Facilitates
FT phosphorylation of T-252 by PDPK1; when
FT associated with E-434; E-441; E-444 and
FT E-447. Mimics phosphorylation. No effect
FT on interaction with PDPK1 and
FT phosphorylation of T-252. Impairs
FT association with the eIF3 complex.
FT MUTAGEN 434 434 S->E: Facilitates phosphorylation of T-
FT 252 by PDPK1; when associated with E-412;
FT E-441; E-444 and E-447.
FT MUTAGEN 441 441 S->E: Facilitates phosphorylation of T-
FT 252 by PDPK1; when associated with E-412;
FT E-434; E-444 and E-447.
FT MUTAGEN 444 444 T->E: Facilitates phosphorylation of T-
FT 252 by PDPK1; when associated with E-412;
FT E-434; E-441 and E-447.
FT MUTAGEN 447 447 S->E: Facilitates phosphorylation of T-
FT 252 by PDPK1; when associated with E-412;
FT E-434; E-441 and E-444.
FT HELIX 88 90
FT STRAND 91 99
FT STRAND 101 110
FT TURN 114 117
FT STRAND 119 127
FT TURN 128 132
FT HELIX 134 149
FT STRAND 158 163
FT STRAND 165 173
FT HELIX 180 187
FT HELIX 192 211
FT HELIX 221 223
FT STRAND 224 226
FT STRAND 232 234
FT STRAND 246 249
FT HELIX 262 266
FT HELIX 273 288
FT HELIX 298 307
FT STRAND 314 316
FT HELIX 318 327
FT HELIX 332 334
FT TURN 340 342
FT HELIX 343 347
FT HELIX 350 352
FT HELIX 357 361
FT HELIX 371 373
FT STRAND 374 377
FT TURN 380 382
FT HELIX 409 411
FT STRAND 413 415
SQ SEQUENCE 525 AA; 59140 MW; 2C3BA13CCDAF4AB3 CRC64;
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
//
MIM
608938
*RECORD*
*FIELD* NO
608938
*FIELD* TI
*608938 RIBOSOMAL PROTEIN S6 KINASE, 70-KD, 1; RPS6KB1
;;S6K1;;
p70 S6 KINASE, ALPHA;;
read morep70(S6K)-ALPHA;;
p70-ALPHA
*FIELD* TX
DESCRIPTION
RPS6KB1 mediates the rapid phosphorylation of ribosomal protein S6
(180460) on multiple serine residues in response to insulin or several
classes of mitogens (Grove et al., 1991).
CLONING
By screening fibroblast and hepatoma cell line cDNA libraries using a
rat Rps6kb1 probe, Grove et al. (1991) cloned 2 splice variants of human
RPS6KB1, which they designated alpha-I and alpha-II. The deduced
proteins contain 525 and 502 amino acids, respectively, and are
identical except for the 23 additional N-terminal residues present in
alpha-I. Exogenous expression of alpha-I cDNA in COS-7 cells resulted in
closely-spaced ladders of polypeptides between 65 and 70 kD and between
85 and 90 kD, whereas expression of the alpha-II cDNA resulted in
peptides between 65 and 70 kD only. Grove et al. (1991) determined that
alpha-I produced both polypeptide clusters by utilizing 2 initiator
methionine codons, the second of which is present in the alpha-II
transcript. The laddering within the 2 clusters was caused
posttranslational modification of the kinase polypeptide by
phosphorylation at multiple sites.
Gout et al. (1998) described the domain organization of the p70 alpha-1
protein, which includes an N-terminal noncatalytic region, a catalytic
domain, a kinase extension domain, an autoinhibitory domain, and a
C-terminal tail. The p70 alpha-1 protein shares 70% amino acid identity
with the p70 beta protein (RPS6KB2; 608939), and 7 serine or threonine
phosphorylation sites are completely conserved. Northern blot analysis
detected 3.4- and 7.4-kb transcripts in all tissues examined.
GENE FUNCTION
Grove et al. (1991) found that transient expression of p70 S6K alpha-I
and alpha-II in COS-7 cells resulted in a 2.5- to 4.0-fold increase in
overall S6 kinase activity. Immunoblot analysis detected alpha-I and
alpha-II as closely spaced ladders of polypeptides between 85 and 90 kD
and between 65 and 70 kD, respectively. Only the alpha-I and alpha-II
proteins of slowest mobility were associated with S6 kinase activity.
The slower mobility and higher enzymatic activity of the rat p70 S6K
proteins were due to serine/threonine phosphorylation, since
phosphatase-2A inactivated the kinase activity and increased the
mobility of the bands on polyacrylamide gels. Grove et al. (1991)
concluded that acquisition of S6 protein kinase catalytic function is
restricted to the most extensively phosphorylated polypeptides.
Gout et al. (1998) examined the catalytic activity of p70 alpha-1
transiently expressed in Chinese hamster ovary cells stably expressing
human insulin receptor (147670). S6 kinase activity was stimulated by
insulin, serum, phorbol ester, and PDGF (see 190040). In transfected
human embryonic kidney cells, serum-activated kinase activity was
potently inhibited by rapamycin and wortmannin in a dose-dependent
manner, suggesting that MTOR (601231) and PI3 kinase (see 602925) are
involved in p70 alpha-1 activation.
Saitoh et al. (1998) characterized p70 S6K-alpha expressed by human
embryonic kidney cells. A 32-mer S6 peptide was phosphorylated by the
wildtype kinase, but not by a catalytically inactivated lys100-to-arg
mutant kinase.
In mammals, MTOR cooperates with PI3K-dependent effectors in a
biochemical signaling pathway to regulate the size of proliferating
cells. Fingar et al. (2002) presented evidence that rat S6k1 alpha-II,
Eif4e (133440), and Eif4ebp1 (602223) mediate Mtor-dependent cell size
control.
Holz et al. (2005) showed that MTOR and S6K1 maneuvered on and off the
EIF3 (see 602039) translation initiation complex in HEK293 cells in a
signal-dependent, choreographed fashion. When inactive, S6K1 associated
with the EIF3 complex, while the S6K1 activator MTOR, in association
with its binding partner RAPTOR (607130), did not. Hormone- or
mitogen-mediated cell stimulation promoted MTOR/RAPTOR binding to the
EIF3 complex and phosphorylation of S6K1. Phosphorylation resulted in
S6K1 dissociation and activation, followed by phosphorylation of S6K1
targets, including EIF4B (603928), which, upon phosphorylation, was
recruited into the EIF3 complex. Holz et al. (2005) concluded that the
EIF3 preinitiation complex acts as a scaffold to coordinate responses to
stimuli that promote efficient protein synthesis.
Dorrello et al. (2006) found that the tumor suppressor programmed cell
death protein-4 (PDCD4; 608610) inhibits the translation initiation
factor EIF4A (see 602641), an RNA helicase that catalyzes the unwinding
of secondary structure at the 5-prime untranslated region of mRNAs. In
response to mitogens, PDCD4 was rapidly phosphorylated on ser67 by the
protein kinase S6K1 and subsequently degraded via the ubiquitin ligase
SCF-beta(TRCP) (603482). Expression in cultured cells of a stable PDCD4
mutant that was unable to bind beta-TRCP inhibited translation of an
mRNA with a structured 5-prime untranslated region, resulted in smaller
cell size, and slowed down cell cycle progression. Dorrello et al.
(2006) proposed that regulated degradation of PDCD4 in response to
mitogens allows efficient protein synthesis and consequently cell
growth.
Robitaille et al. (2013) found that mTORC1 indirectly phosphorylates the
trifunctional protein CAD (carbamoyl phosphate synthetase-2/aspartate
transcarbamoylase/ dihydroorotase; 114010), which catalyzes the first 3
steps in de novo pyrimidine synthesis, on residue S1859 through S6K.
CAD-S1859 phosphorylation promoted CAD oligomerization and thereby
stimulated de novo synthesis of pyrimidines and progression through S
phase of the cell cycle in mammalian cells. Ben-Sahra et al. (2013)
independently showed that activation of mTORC1 led to the acute
stimulation of metabolic flux through the de novo pyrimidine synthesis
pathway. mTORC1 signaling posttranslationally regulated this metabolic
pathway via its downstream target S6K1, which directly phosphorylates
S1859 on CAD. Growth signaling through mTORC1 thus stimulates the
production of new nucleotides to accommodate an increase in RNA and DNA
synthesis needed for ribosome biogenesis and anabolic growth.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the RPS6KB1
gene to chromosome 17 (TMAP SHGC-34099).
ANIMAL MODEL
Shima et al. (1998) generated mice deficient in S6k1 by targeted
disruption. These mice were viable and fertile, but exhibited a
conspicuous reduction in body size during embryogenesis, an effect that
was mostly overcome by adulthood. Shima et al. (1998) hypothesized that
the weak penetrance of the phenotype may arise from increased expression
in S6k1-deficient mice of the highly homologous gene S6k2.
Pende et al. (2000) showed that mice deficient for S6k1, a known
effector of the phosphatidylinositide-3-OH kinase signaling pathway,
were hypoinsulinemic and glucose intolerant. Whereas insulin resistance
was not observed in isolated muscle, such mice exhibited a sharp
reduction in glucose-induced insulin secretion and in pancreatic insulin
content. This was not due to a lesion in glucose sensing or insulin
production, but to a reduction in pancreatic endocrine mass, which was
accounted for by a selective decrease in beta-cell size. Pende et al.
(2000) concluded that the observed phenotype closely parallels those of
preclinical type II diabetes mellitus, in which malnutrition-induced
hypoinsulinemia predisposes individuals to glucose intolerance.
Pende et al. (2004) found that mice deficient in S6k1 or S6k2 were born
at expected mendelian ratios. Compared with wildtype mice, S6k1 -/- mice
were significantly smaller, and S6k2 -/- mice tended to be slightly
larger. Mice lacking both genes showed a sharp reduction in viability
due to perinatal lethality. Analysis of S6 phosphorylation in the
cytoplasm and nucleoli of cells derived from each S6k genotype suggested
that both kinases are required for full S6 phosphorylation, but that
S6k2 may contribute more to the response. Despite the impairment of S6
phosphorylation in cells from double-knockout mice, cell cycle
progression and translation of 5-prime terminal oligopyrimidine mRNAs
were still modulated by mitogens in a rapamycin-dependent manner.
Double-knockout cells also showed persistence of S6 phosphorylation on
the first 2 serines phosphorylated in response to mitogens, and this
step was catalyzed by a MAPK-dependent kinase. Pende et al. (2004)
concluded that a redundancy exists between the S6K and MAPK pathways in
mediating early S6 phosphorylation in response to mitogens.
Um et al. (2004) reported that S6k1-deficient mice are protected against
obesity due to enhanced beta-oxidation; however, on a high-fat diet,
levels of glucose and free fatty acids still rose in S6k1-deficient
mice, resulting in insulin receptor desensitization. Nevertheless,
S6k1-deficient mice remained sensitive to insulin due to the apparent
loss of a negative feedback loop from S6k1 to insulin receptor
substrate-1 (IRS1; 147545), which blunts phosphorylation of serines at
positions 307, 636, and 639, all sites involved in insulin resistance.
Moreover, wildtype mice on a high-fat diet as well as K/K A(y) and ob/ob
mice had markedly elevated S6k1 activity and, unlike S6k1-deficient
mice, increased phosphorylation of Irs1 serines at positions 307, 636,
and 639. Um et al. (2004) concluded that under conditions of nutrient
satiation, S6K1 negatively regulates insulin signaling.
Selman et al. (2009) demonstrated in mice that deletion of S6K1, a
component of the nutrient-responsive mTOR signaling pathway, led to
increased life span and resistance to age-related pathologies such as
bone, immune, and motor dysfunction and loss of insulin sensitivity.
Deletion of S6K1 induced gene expression patterns similar to those seen
in caloric restriction or with pharmacologic activation of adenosine
monophosphate (AMP)-activated protein kinase (AMPK), a conserved
regulator of the metabolic response to caloric restriction.
*FIELD* RF
1. Ben-Sahra, I.; Howell, J. J.; Asara, J. M.; Manning, B. D.: Stimulation
of de novo pyrimidine synthesis by growth signaling through mTOR and
S6K1. Science 339: 1323-1328, 2013.
2. Dorrello, N. V.; Peschiaroli, A.; Guardavaccaro, D.; Colburn, N.
H.; Sherman, N. E.; Pagano, M.: S6K1- and beta-TRCP-mediated degradation
of PDCD4 promotes protein translation and cell growth. Science 314:
467-471, 2006.
3. Fingar, D. C.; Salama, S.; Tsou, C.; Harlow, E.; Blenis, J.: Mammalian
cell size is controlled by mTOR and its downstream targets S6K1 and
4EBP1/eIF4E. Genes Dev. 16: 1472-1487, 2002.
4. Gout, I.; Minami, T.; Hara, K.; Tsujishita, Y.; Filonenko, V.;
Waterfield, M. D.; Yonezawa, K.: Molecular cloning and characterization
of a novel p70 S6 kinase, p70 S6 kinase beta containing a proline-rich
region. J. Biol. Chem. 273: 30061-30064, 1998.
5. Grove, J. R.; Banerjee, P.; Balasubramanyam, A.; Coffer, P. J.;
Price, D. J.; Avruch, J.; Woodgett, J. R.: Cloning and expression
of two human p70 S6 kinase polypeptides differing only at their amino
termini. Molec. Cell. Biol. 11: 5541-5550, 1991.
6. Holz, M. K.; Ballif, B. A.; Gygi, S. P.; Blenis, J.: mTOR and
S6K1 mediate assembly of the translation preinitiation complex through
dynamic protein interchange and ordered phosphorylation events. Cell 123:
569-580, 2005.
7. Pende, M.; Kozma, S. C.; Jaquet, M.; Oorschot, V.; Burcelin, R.;
Le Marchand-Brustel, Y.; Klumperman, J.; Thorens, B.; Thomas, G.:
Hypoinsulinaemia, glucose intolerance and diminished beta-cell size
in S6K1-deficient mice. Nature 408: 994-997, 2000.
8. Pende, M.; Um, S. H.; Mieulet, V.; Sticker, M.; Goss, V. L.; Mestan,
J.; Mueller, M.; Fumagalli, S.; Kozma, S. C.; Thomas, G.: S6K1-/-/S6K2-/-
mice exhibit perinatal lethality and rapamycin-sensitive 5-prime-terminal
oligopyrimidine mRNA translation and reveal a mitogen-activated protein
kinase-dependent S6 kinase pathway. Molec. Cell. Biol. 24: 3112-3124,
2004.
9. Robitaille, A. M.; Christen, S.; Shimobayashi, M.; Cornu, M.; Fava,
L. L.; Moes, S.; Prescianotto-Baschong, C.; Sauer, U.; Jenoe, P.;
Hall, M. N.: Quantitative phosphoproteomics reveal mTORC1 activates
de novo pyrimidine synthesis. Science 339: 1320-1323, 2013.
10. Saitoh, M.; ten Dijke, P.; Miyazono, K.; Ichijo, H.: Cloning
and characterization of p70(S6K-beta) defines a novel family of p70
S6 kinases. Biochem. Biophys. Res. Commun. 253: 470-476, 1998.
11. Selman, C.; Tullet, J. M. A.; Wieser, D.; Irvine, E.; Lingard,
S. J.; Choudhury, A. I.; Claret, M.; Al-Qassab, H.; Carmignac, D.;
Ramadani, F.; Woods, A.; Robinson, I. C. A.; and 10 others: Ribosomal
protein S6 kinase 1 signaling regulates mammalian life span. Science 326:
140-144, 2009. Note: Erratum: Science 334: 39 only, 2011.
12. Shima, H.; Pende, M.; Chen, Y.; Fumagalli, S.; Thomas, G.; Kozma,
S. C.: Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse
phenotype and a new functional S6 kinase. EMBO J. 17: 6649-6659,
1998.
13. Um, S. H.; Frigerio, F.; Watanabe, M.; Picard, F.; Joaquin, M.;
Sticker, M.; Fumagalli, S.; Allegrini, P. R.; Kozma, S. C.; Auwerx,
J.; Thomas, G.: Absence of S6K1 protects against age- and diet-induced
obesity while enhancing insulin sensitivity. Nature 431: 200-205,
2004. Note: Erratum: Nature 431: 485 only, 2004.
*FIELD* CN
Ada Hamosh - updated: 07/08/2013
Ada Hamosh - updated: 11/13/2009
Patricia A. Hartz - updated: 5/5/2009
Ada Hamosh - updated: 10/31/2006
Ada Hamosh - updated: 11/29/2004
Ada Hamosh - updated: 9/29/2004
*FIELD* CD
Patricia A. Hartz: 9/22/2004
*FIELD* ED
alopez: 07/08/2013
terry: 9/14/2012
alopez: 11/16/2009
terry: 11/13/2009
mgross: 5/5/2009
terry: 5/5/2009
alopez: 11/6/2006
terry: 10/31/2006
tkritzer: 11/29/2004
terry: 11/29/2004
tkritzer: 9/30/2004
terry: 9/29/2004
mgross: 9/23/2004
mgross: 9/22/2004
*RECORD*
*FIELD* NO
608938
*FIELD* TI
*608938 RIBOSOMAL PROTEIN S6 KINASE, 70-KD, 1; RPS6KB1
;;S6K1;;
p70 S6 KINASE, ALPHA;;
read morep70(S6K)-ALPHA;;
p70-ALPHA
*FIELD* TX
DESCRIPTION
RPS6KB1 mediates the rapid phosphorylation of ribosomal protein S6
(180460) on multiple serine residues in response to insulin or several
classes of mitogens (Grove et al., 1991).
CLONING
By screening fibroblast and hepatoma cell line cDNA libraries using a
rat Rps6kb1 probe, Grove et al. (1991) cloned 2 splice variants of human
RPS6KB1, which they designated alpha-I and alpha-II. The deduced
proteins contain 525 and 502 amino acids, respectively, and are
identical except for the 23 additional N-terminal residues present in
alpha-I. Exogenous expression of alpha-I cDNA in COS-7 cells resulted in
closely-spaced ladders of polypeptides between 65 and 70 kD and between
85 and 90 kD, whereas expression of the alpha-II cDNA resulted in
peptides between 65 and 70 kD only. Grove et al. (1991) determined that
alpha-I produced both polypeptide clusters by utilizing 2 initiator
methionine codons, the second of which is present in the alpha-II
transcript. The laddering within the 2 clusters was caused
posttranslational modification of the kinase polypeptide by
phosphorylation at multiple sites.
Gout et al. (1998) described the domain organization of the p70 alpha-1
protein, which includes an N-terminal noncatalytic region, a catalytic
domain, a kinase extension domain, an autoinhibitory domain, and a
C-terminal tail. The p70 alpha-1 protein shares 70% amino acid identity
with the p70 beta protein (RPS6KB2; 608939), and 7 serine or threonine
phosphorylation sites are completely conserved. Northern blot analysis
detected 3.4- and 7.4-kb transcripts in all tissues examined.
GENE FUNCTION
Grove et al. (1991) found that transient expression of p70 S6K alpha-I
and alpha-II in COS-7 cells resulted in a 2.5- to 4.0-fold increase in
overall S6 kinase activity. Immunoblot analysis detected alpha-I and
alpha-II as closely spaced ladders of polypeptides between 85 and 90 kD
and between 65 and 70 kD, respectively. Only the alpha-I and alpha-II
proteins of slowest mobility were associated with S6 kinase activity.
The slower mobility and higher enzymatic activity of the rat p70 S6K
proteins were due to serine/threonine phosphorylation, since
phosphatase-2A inactivated the kinase activity and increased the
mobility of the bands on polyacrylamide gels. Grove et al. (1991)
concluded that acquisition of S6 protein kinase catalytic function is
restricted to the most extensively phosphorylated polypeptides.
Gout et al. (1998) examined the catalytic activity of p70 alpha-1
transiently expressed in Chinese hamster ovary cells stably expressing
human insulin receptor (147670). S6 kinase activity was stimulated by
insulin, serum, phorbol ester, and PDGF (see 190040). In transfected
human embryonic kidney cells, serum-activated kinase activity was
potently inhibited by rapamycin and wortmannin in a dose-dependent
manner, suggesting that MTOR (601231) and PI3 kinase (see 602925) are
involved in p70 alpha-1 activation.
Saitoh et al. (1998) characterized p70 S6K-alpha expressed by human
embryonic kidney cells. A 32-mer S6 peptide was phosphorylated by the
wildtype kinase, but not by a catalytically inactivated lys100-to-arg
mutant kinase.
In mammals, MTOR cooperates with PI3K-dependent effectors in a
biochemical signaling pathway to regulate the size of proliferating
cells. Fingar et al. (2002) presented evidence that rat S6k1 alpha-II,
Eif4e (133440), and Eif4ebp1 (602223) mediate Mtor-dependent cell size
control.
Holz et al. (2005) showed that MTOR and S6K1 maneuvered on and off the
EIF3 (see 602039) translation initiation complex in HEK293 cells in a
signal-dependent, choreographed fashion. When inactive, S6K1 associated
with the EIF3 complex, while the S6K1 activator MTOR, in association
with its binding partner RAPTOR (607130), did not. Hormone- or
mitogen-mediated cell stimulation promoted MTOR/RAPTOR binding to the
EIF3 complex and phosphorylation of S6K1. Phosphorylation resulted in
S6K1 dissociation and activation, followed by phosphorylation of S6K1
targets, including EIF4B (603928), which, upon phosphorylation, was
recruited into the EIF3 complex. Holz et al. (2005) concluded that the
EIF3 preinitiation complex acts as a scaffold to coordinate responses to
stimuli that promote efficient protein synthesis.
Dorrello et al. (2006) found that the tumor suppressor programmed cell
death protein-4 (PDCD4; 608610) inhibits the translation initiation
factor EIF4A (see 602641), an RNA helicase that catalyzes the unwinding
of secondary structure at the 5-prime untranslated region of mRNAs. In
response to mitogens, PDCD4 was rapidly phosphorylated on ser67 by the
protein kinase S6K1 and subsequently degraded via the ubiquitin ligase
SCF-beta(TRCP) (603482). Expression in cultured cells of a stable PDCD4
mutant that was unable to bind beta-TRCP inhibited translation of an
mRNA with a structured 5-prime untranslated region, resulted in smaller
cell size, and slowed down cell cycle progression. Dorrello et al.
(2006) proposed that regulated degradation of PDCD4 in response to
mitogens allows efficient protein synthesis and consequently cell
growth.
Robitaille et al. (2013) found that mTORC1 indirectly phosphorylates the
trifunctional protein CAD (carbamoyl phosphate synthetase-2/aspartate
transcarbamoylase/ dihydroorotase; 114010), which catalyzes the first 3
steps in de novo pyrimidine synthesis, on residue S1859 through S6K.
CAD-S1859 phosphorylation promoted CAD oligomerization and thereby
stimulated de novo synthesis of pyrimidines and progression through S
phase of the cell cycle in mammalian cells. Ben-Sahra et al. (2013)
independently showed that activation of mTORC1 led to the acute
stimulation of metabolic flux through the de novo pyrimidine synthesis
pathway. mTORC1 signaling posttranslationally regulated this metabolic
pathway via its downstream target S6K1, which directly phosphorylates
S1859 on CAD. Growth signaling through mTORC1 thus stimulates the
production of new nucleotides to accommodate an increase in RNA and DNA
synthesis needed for ribosome biogenesis and anabolic growth.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the RPS6KB1
gene to chromosome 17 (TMAP SHGC-34099).
ANIMAL MODEL
Shima et al. (1998) generated mice deficient in S6k1 by targeted
disruption. These mice were viable and fertile, but exhibited a
conspicuous reduction in body size during embryogenesis, an effect that
was mostly overcome by adulthood. Shima et al. (1998) hypothesized that
the weak penetrance of the phenotype may arise from increased expression
in S6k1-deficient mice of the highly homologous gene S6k2.
Pende et al. (2000) showed that mice deficient for S6k1, a known
effector of the phosphatidylinositide-3-OH kinase signaling pathway,
were hypoinsulinemic and glucose intolerant. Whereas insulin resistance
was not observed in isolated muscle, such mice exhibited a sharp
reduction in glucose-induced insulin secretion and in pancreatic insulin
content. This was not due to a lesion in glucose sensing or insulin
production, but to a reduction in pancreatic endocrine mass, which was
accounted for by a selective decrease in beta-cell size. Pende et al.
(2000) concluded that the observed phenotype closely parallels those of
preclinical type II diabetes mellitus, in which malnutrition-induced
hypoinsulinemia predisposes individuals to glucose intolerance.
Pende et al. (2004) found that mice deficient in S6k1 or S6k2 were born
at expected mendelian ratios. Compared with wildtype mice, S6k1 -/- mice
were significantly smaller, and S6k2 -/- mice tended to be slightly
larger. Mice lacking both genes showed a sharp reduction in viability
due to perinatal lethality. Analysis of S6 phosphorylation in the
cytoplasm and nucleoli of cells derived from each S6k genotype suggested
that both kinases are required for full S6 phosphorylation, but that
S6k2 may contribute more to the response. Despite the impairment of S6
phosphorylation in cells from double-knockout mice, cell cycle
progression and translation of 5-prime terminal oligopyrimidine mRNAs
were still modulated by mitogens in a rapamycin-dependent manner.
Double-knockout cells also showed persistence of S6 phosphorylation on
the first 2 serines phosphorylated in response to mitogens, and this
step was catalyzed by a MAPK-dependent kinase. Pende et al. (2004)
concluded that a redundancy exists between the S6K and MAPK pathways in
mediating early S6 phosphorylation in response to mitogens.
Um et al. (2004) reported that S6k1-deficient mice are protected against
obesity due to enhanced beta-oxidation; however, on a high-fat diet,
levels of glucose and free fatty acids still rose in S6k1-deficient
mice, resulting in insulin receptor desensitization. Nevertheless,
S6k1-deficient mice remained sensitive to insulin due to the apparent
loss of a negative feedback loop from S6k1 to insulin receptor
substrate-1 (IRS1; 147545), which blunts phosphorylation of serines at
positions 307, 636, and 639, all sites involved in insulin resistance.
Moreover, wildtype mice on a high-fat diet as well as K/K A(y) and ob/ob
mice had markedly elevated S6k1 activity and, unlike S6k1-deficient
mice, increased phosphorylation of Irs1 serines at positions 307, 636,
and 639. Um et al. (2004) concluded that under conditions of nutrient
satiation, S6K1 negatively regulates insulin signaling.
Selman et al. (2009) demonstrated in mice that deletion of S6K1, a
component of the nutrient-responsive mTOR signaling pathway, led to
increased life span and resistance to age-related pathologies such as
bone, immune, and motor dysfunction and loss of insulin sensitivity.
Deletion of S6K1 induced gene expression patterns similar to those seen
in caloric restriction or with pharmacologic activation of adenosine
monophosphate (AMP)-activated protein kinase (AMPK), a conserved
regulator of the metabolic response to caloric restriction.
*FIELD* RF
1. Ben-Sahra, I.; Howell, J. J.; Asara, J. M.; Manning, B. D.: Stimulation
of de novo pyrimidine synthesis by growth signaling through mTOR and
S6K1. Science 339: 1323-1328, 2013.
2. Dorrello, N. V.; Peschiaroli, A.; Guardavaccaro, D.; Colburn, N.
H.; Sherman, N. E.; Pagano, M.: S6K1- and beta-TRCP-mediated degradation
of PDCD4 promotes protein translation and cell growth. Science 314:
467-471, 2006.
3. Fingar, D. C.; Salama, S.; Tsou, C.; Harlow, E.; Blenis, J.: Mammalian
cell size is controlled by mTOR and its downstream targets S6K1 and
4EBP1/eIF4E. Genes Dev. 16: 1472-1487, 2002.
4. Gout, I.; Minami, T.; Hara, K.; Tsujishita, Y.; Filonenko, V.;
Waterfield, M. D.; Yonezawa, K.: Molecular cloning and characterization
of a novel p70 S6 kinase, p70 S6 kinase beta containing a proline-rich
region. J. Biol. Chem. 273: 30061-30064, 1998.
5. Grove, J. R.; Banerjee, P.; Balasubramanyam, A.; Coffer, P. J.;
Price, D. J.; Avruch, J.; Woodgett, J. R.: Cloning and expression
of two human p70 S6 kinase polypeptides differing only at their amino
termini. Molec. Cell. Biol. 11: 5541-5550, 1991.
6. Holz, M. K.; Ballif, B. A.; Gygi, S. P.; Blenis, J.: mTOR and
S6K1 mediate assembly of the translation preinitiation complex through
dynamic protein interchange and ordered phosphorylation events. Cell 123:
569-580, 2005.
7. Pende, M.; Kozma, S. C.; Jaquet, M.; Oorschot, V.; Burcelin, R.;
Le Marchand-Brustel, Y.; Klumperman, J.; Thorens, B.; Thomas, G.:
Hypoinsulinaemia, glucose intolerance and diminished beta-cell size
in S6K1-deficient mice. Nature 408: 994-997, 2000.
8. Pende, M.; Um, S. H.; Mieulet, V.; Sticker, M.; Goss, V. L.; Mestan,
J.; Mueller, M.; Fumagalli, S.; Kozma, S. C.; Thomas, G.: S6K1-/-/S6K2-/-
mice exhibit perinatal lethality and rapamycin-sensitive 5-prime-terminal
oligopyrimidine mRNA translation and reveal a mitogen-activated protein
kinase-dependent S6 kinase pathway. Molec. Cell. Biol. 24: 3112-3124,
2004.
9. Robitaille, A. M.; Christen, S.; Shimobayashi, M.; Cornu, M.; Fava,
L. L.; Moes, S.; Prescianotto-Baschong, C.; Sauer, U.; Jenoe, P.;
Hall, M. N.: Quantitative phosphoproteomics reveal mTORC1 activates
de novo pyrimidine synthesis. Science 339: 1320-1323, 2013.
10. Saitoh, M.; ten Dijke, P.; Miyazono, K.; Ichijo, H.: Cloning
and characterization of p70(S6K-beta) defines a novel family of p70
S6 kinases. Biochem. Biophys. Res. Commun. 253: 470-476, 1998.
11. Selman, C.; Tullet, J. M. A.; Wieser, D.; Irvine, E.; Lingard,
S. J.; Choudhury, A. I.; Claret, M.; Al-Qassab, H.; Carmignac, D.;
Ramadani, F.; Woods, A.; Robinson, I. C. A.; and 10 others: Ribosomal
protein S6 kinase 1 signaling regulates mammalian life span. Science 326:
140-144, 2009. Note: Erratum: Science 334: 39 only, 2011.
12. Shima, H.; Pende, M.; Chen, Y.; Fumagalli, S.; Thomas, G.; Kozma,
S. C.: Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse
phenotype and a new functional S6 kinase. EMBO J. 17: 6649-6659,
1998.
13. Um, S. H.; Frigerio, F.; Watanabe, M.; Picard, F.; Joaquin, M.;
Sticker, M.; Fumagalli, S.; Allegrini, P. R.; Kozma, S. C.; Auwerx,
J.; Thomas, G.: Absence of S6K1 protects against age- and diet-induced
obesity while enhancing insulin sensitivity. Nature 431: 200-205,
2004. Note: Erratum: Nature 431: 485 only, 2004.
*FIELD* CN
Ada Hamosh - updated: 07/08/2013
Ada Hamosh - updated: 11/13/2009
Patricia A. Hartz - updated: 5/5/2009
Ada Hamosh - updated: 10/31/2006
Ada Hamosh - updated: 11/29/2004
Ada Hamosh - updated: 9/29/2004
*FIELD* CD
Patricia A. Hartz: 9/22/2004
*FIELD* ED
alopez: 07/08/2013
terry: 9/14/2012
alopez: 11/16/2009
terry: 11/13/2009
mgross: 5/5/2009
terry: 5/5/2009
alopez: 11/6/2006
terry: 10/31/2006
tkritzer: 11/29/2004
terry: 11/29/2004
tkritzer: 9/30/2004
terry: 9/29/2004
mgross: 9/23/2004
mgross: 9/22/2004