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Gene Review

Rps6kb1  -  ribosomal protein S6 kinase, polypeptide 1

Mus musculus

Synonyms: 2610318I15Rik, 4732464A07Rik, 70 kDa ribosomal protein S6 kinase 1, 70kDa, AA959758, ...
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Disease relevance of Rps6kb1


Psychiatry related information on Rps6kb1

  • Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling [5].

High impact information on Rps6kb1

  • The 70 kDa ribosomol S6 kinase (pp70S6k) plays an important role in the progression of cells through G1 phase of the cell cycle [6].
  • Detailed kinetics reveal that EGF-induced S6 kinase activation is biphasic: an early phase appears at 10-15 min, followed by a late phase between 30 and 60 min [7].
  • Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice [8].
  • The critical autophosphorylation site for p70s6k/p85s6k activation within this domain is a tyrosine at residue 751 [9].
  • A mitogen-activated S6 kinase of relative molecular mass 70,000 (70K) has been isolated from mouse fibroblasts as well as from avian, rat and rabbit tissues [10].

Chemical compound and disease context of Rps6kb1


Biological context of Rps6kb1


Anatomical context of Rps6kb1


Associations of Rps6kb1 with chemical compounds

  • The mammalian target of rapamycin activity (measured as phospho-p70S6 kinase) was activated by LPS but not significantly blocked by LY2 [20].
  • Upon mu-opioid receptor stimulation, p70 S6 kinase is activated and phosphorylated at threonine 389 and at threonine 421/serine 424 [21].
  • This selective synaptic activation of mTOR-S6K is also resistant to APV and inhibited by Ca(2+) channel blockers and higher concentrations of glutamate [22].
  • Several S6 kinase agonists not previously known to activate phosphatidylinositol 3-kinase (A23187, bombesin and phorbol 12-myristate 13-acetate) were found to increase the production of phosphatidylinositol 3,4,5-trisphosphate in a wortmannin-sensitive manner [23].
  • However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization [5].

Physical interactions of Rps6kb1


Enzymatic interactions of Rps6kb1


Regulatory relationships of Rps6kb1

  • Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression [27].
  • Likewise suppression of p70S6 kinase with rapamycin down-regulated phagocytic efficiency conferred by the expression of constitutively active Akt [28].
  • In contrast, the impact of SHIP2 expression was diminished in insulin-induced phosphorylation of p70S6-kinase and S6, but not of Akt, after the incubation for 16 h [29].
  • The expression of DNM-Akt1 also suppressed EGF-induced p70 S6K activation as well as Akt activation [30].
  • Consistently, Gas6 activates the P13K downstream targets S6K and Akt, whose activation is abrogated by addition of wortmannin [31].

Other interactions of Rps6kb1

  • mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF [16].
  • Compared to wild-type mice, S6K1(-/-) mice are significantly smaller, whereas S6K2(-/-) mice tend to be slightly larger [14].
  • In contrast, sustained glutamatergic stimulation inhibits ERK, Akt, and S6K [22].
  • These findings provide genetic evidence that the phosphate groove of PDK1 is required for maximal activation of isoforms of S6K, SGK and RSK, but not PKC [32].
  • The considerable residual differentiation in the presence of rapamycin, despite the complete blockade of p70 S6K activation, prompted us to measure the phosphorylation of another rapamycin-sensitive protein, eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) [33].

Analytical, diagnostic and therapeutic context of Rps6kb1

  • Western-blot analysis and immunocomplex kinase assays showed that wortmannin and demethoxyviridin specifically block the phosphorylation and activation of p70 S6 kinase without affecting the M(r) 90,000 ribosomal S6 kinase (p90rsk) or mitogen-activated protein kinases [23].
  • Microinjection of highly specific inhibitors of PI3K or Rac1, or treatment with the p70s6k inhibitor rapamycin, impaired cAMP-stimulated DNA synthesis, demonstrating that PKA-dependent and -independent pathways contribute to cAMP-mediated mitogenesis [34].
  • Pituitary growth hormone (GH) co-ordinately stimulates three distinct signalling pathways in 3T3-F442A preadipocytes, the STAT (signal transducer and activator of transcription) pathway, the mitogen-activated protein (MAP) kinase cascade and p70s6k [35].
  • All the mutants strongly activated Akt and p70S6K compared with wild-type p110alpha as determined by immunoblotting using phospho-specific antibodies [36].
  • Alterations in the degree of the phosphorylation of ERKI/2, Akt-1 and p70 S6K in mouse skeletal and cardiac muscle was examined in vivo following an intraperitoneal injection of des IGF-I [37].


  1. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. Harrington, L.S., Findlay, G.M., Gray, A., Tolkacheva, T., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N.R., Cheng, S., Shepherd, P.R., Gout, I., Downes, C.P., Lamb, R.F. J. Cell Biol. (2004) [Pubmed]
  2. Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy. McMullen, J.R., Shioi, T., Zhang, L., Tarnavski, O., Sherwood, M.C., Dorfman, A.L., Longnus, S., Pende, M., Martin, K.A., Blenis, J., Thomas, G., Izumo, S. Mol. Cell. Biol. (2004) [Pubmed]
  3. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Kwiatkowski, D.J., Zhang, H., Bandura, J.L., Heiberger, K.M., Glogauer, M., el-Hashemite, N., Onda, H. Hum. Mol. Genet. (2002) [Pubmed]
  4. Suppression of PI3K/mTOR pathway rescues LLC cells from cell death induced by hypoxia. Hamanaka, Y., Mukai, M., Shimamura, M., Kitagawa, T., Nishida, T., Isohashi, F., Ito, T., Nishizawa, Y., Tatsuta, M., Matsuda, H., Inoue, M. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  5. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. 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. Nature (2004) [Pubmed]
  6. The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1. Chou, M.M., Blenis, J. Cell (1996) [Pubmed]
  7. EGF induces biphasic S6 kinase activation: late phase is protein kinase C-dependent and contributes to mitogenicity. Susa, M., Olivier, A.R., Fabbro, D., Thomas, G. Cell (1989) [Pubmed]
  8. Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Pende, M., Kozma, S.C., Jaquet, M., Oorschot, V., Burcelin, R., Le Marchand-Brustel, Y., Klumperman, J., Thorens, B., Thomas, G. Nature (2000) [Pubmed]
  9. Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Ming, X.F., Burgering, B.M., Wennström, S., Claesson-Welsh, L., Heldin, C.H., Bos, J.L., Kozma, S.C., Thomas, G. Nature (1994) [Pubmed]
  10. MAP2 kinase and 70K S6 kinase lie on distinct signalling pathways. Ballou, L.M., Luther, H., Thomas, G. Nature (1991) [Pubmed]
  11. Participation of a MEK-independent pathway in MAP kinase activation and modulation of cell growth in mouse hepatoma cell lines. Saeki, Y., Hazeki, K., Hazeki, O., Ui, M., Itoh, K., Matsumoto, M., Toyoshima, K., Akedo, H., Seya, T. Int. J. Mol. Med. (2000) [Pubmed]
  12. Vascular hypertrophy and increased P70S6 kinase in mice lacking the angiotensin II AT(2) receptor. Brede, M., Hadamek, K., Meinel, L., Wiesmann, F., Peters, J., Engelhardt, S., Simm, A., Haase, A., Lohse, M.J., Hein, L. Circulation (2001) [Pubmed]
  13. Role of S6 phosphorylation and S6 kinase in cell growth. Volarević, S., Thomas, G. Prog. Nucleic Acid Res. Mol. Biol. (2001) [Pubmed]
  14. S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Pende, M., Um, S.H., Mieulet, V., Sticker, M., Goss, V.L., Mestan, J., Mueller, M., Fumagalli, S., Kozma, S.C., Thomas, G. Mol. Cell. Biol. (2004) [Pubmed]
  15. Translational homeostasis: eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities. Khaleghpour, K., Pyronnet, S., Gingras, A.C., Sonenberg, N. Mol. Cell. Biol. (1999) [Pubmed]
  16. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Hannan, K.M., Brandenburger, Y., Jenkins, A., Sharkey, K., Cavanaugh, A., Rothblum, L., Moss, T., Poortinga, G., McArthur, G.A., Pearson, R.B., Hannan, R.D. Mol. Cell. Biol. (2003) [Pubmed]
  17. M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Glantschnig, H., Fisher, J.E., Wesolowski, G., Rodan, G.A., Reszka, A.A. Cell Death Differ. (2003) [Pubmed]
  18. Mechanism of ribosomal p70S6 kinase activation by granulocyte macrophage colony-stimulating factor in neutrophils: cooperation of a MEK-related, THR421/SER424 kinase and a rapamycin-sensitive, m-TOR-related THR389 kinase. Lehman, J.A., Calvo, V., Gomez-Cambronero, J. J. Biol. Chem. (2003) [Pubmed]
  19. Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Berven, L.A., Willard, F.S., Crouch, M.F. Exp. Cell Res. (2004) [Pubmed]
  20. Signaling in lipopolysaccharide-induced stabilization of formyl Peptide receptor 1 mRNA in mouse peritoneal macrophages. Mandal, P., Hamilton, T. J. Immunol. (2007) [Pubmed]
  21. mu-Opioid receptor activates signaling pathways implicated in cell survival and translational control. Polakiewicz, R.D., Schieferl, S.M., Gingras, A.C., Sonenberg, N., Comb, M.J. J. Biol. Chem. (1998) [Pubmed]
  22. Glutamatergic regulation of the p70S6 kinase in primary mouse neurons. Lenz, G., Avruch, J. J. Biol. Chem. (2005) [Pubmed]
  23. Selective inhibition of p70 S6 kinase activation by phosphatidylinositol 3-kinase inhibitors. Petritsch, C., Woscholski, R., Edelmann, H.M., Parker, P.J., Ballou, L.M. Eur. J. Biochem. (1995) [Pubmed]
  24. Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation. Uhlmann, E.J., Li, W., Scheidenhelm, D.K., Gau, C.L., Tamanoi, F., Gutmann, D.H. Glia (2004) [Pubmed]
  25. Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes. MacKenzie, S.J., Yarwood, S.J., Peden, A.H., Bolger, G.B., Vernon, R.G., Houslay, M.D. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  26. Involvement of p70 S6 kinase in bone morphogenetic protein signaling: vascular endothelial growth factor synthesis by bone morphogenetic protein-4 in osteoblasts. Kozawa, O., Matsuno, H., Uematsu, T. J. Cell. Biochem. (2001) [Pubmed]
  27. Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression. Chou, M.M., Masuda-Robens, J.M., Gupta, M.L. J. Biol. Chem. (2003) [Pubmed]
  28. The serine/threonine kinase Akt Promotes Fc gamma receptor-mediated phagocytosis in murine macrophages through the activation of p70S6 kinase. Ganesan, L.P., Wei, G., Pengal, R.A., Moldovan, L., Moldovan, N., Ostrowski, M.C., Tridandapani, S. J. Biol. Chem. (2004) [Pubmed]
  29. Impact of Src homology 2-containing inositol 5'-phosphatase 2 on the regulation of insulin signaling leading to protein synthesis in 3T3-L1 adipocytes cultured with excess amino acids. Murakami, S., Sasaoka, T., Wada, T., Fukui, K., Nagira, K., Ishihara, H., Usui, I., Kobayashi, M. Endocrinology (2004) [Pubmed]
  30. Involvement of the Akt/mTOR pathway on EGF-induced cell transformation. Nomura, M., He, Z., Koyama, I., Ma, W.Y., Miyamoto, K., Dong, Z. Mol. Carcinog. (2003) [Pubmed]
  31. Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts. Goruppi, S., Ruaro, E., Varnum, B., Schneider, C. Mol. Cell. Biol. (1997) [Pubmed]
  32. In vivo role of the phosphate groove of PDK1 defined by knockin mutation. Collins, B.J., Deak, M., Murray-Tait, V., Storey, K.G., Alessi, D.R. J. Cell. Sci. (2005) [Pubmed]
  33. Inhibition of insulin signaling and adipogenesis by rapamycin: effect on phosphorylation of p70 S6 kinase vs eIF4E-BP1. El-Chaâr, D., Gagnon, A., Sorisky, A. Int. J. Obes. Relat. Metab. Disord. (2004) [Pubmed]
  34. Protein kinase A-dependent and -independent signaling pathways contribute to cyclic AMP-stimulated proliferation. Cass, L.A., Summers, S.A., Prendergast, G.V., Backer, J.M., Birnbaum, M.J., Meinkoth, J.L. Mol. Cell. Biol. (1999) [Pubmed]
  35. Requirement for phosphoinositide 3-OH kinase in growth hormone signalling to the mitogen-activated protein kinase and p70s6k pathways. Kilgour, E., Gout, I., Anderson, N.G. Biochem. J. (1996) [Pubmed]
  36. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Ikenoue, T., Kanai, F., Hikiba, Y., Obata, T., Tanaka, Y., Imamura, J., Ohta, M., Jazag, A., Guleng, B., Tateishi, K., Asaoka, Y., Matsumura, M., Kawabe, T., Omata, M. Cancer Res. (2005) [Pubmed]
  37. Differential effects of des IGF-1 on Erks, AKT-1 and P70 S6K activation in mouse skeletal and cardiac muscle. Li, M., Li, C., Parkhouse, W.S. Mol. Cell. Biochem. (2002) [Pubmed]
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