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Gene Review

RPS6KA1  -  ribosomal protein S6 kinase, 90kDa,...

Homo sapiens

Synonyms: 90 kDa ribosomal protein S6 kinase 1, HU-1, MAP kinase-activated protein kinase 1a, MAPK-activated protein kinase 1a, MAPKAP kinase 1a, ...
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Disease relevance of RPS6KA1

  • These results suggest that proliferation of some prostate cancer cells is dependent on RSK activity and support the hypothesis that RSK may be an important chemotherapeutic target for prostate cancer [1].
  • Importantly, ectopic expression of a constitutively activated RSK mutant abrogates Bad activation and renders melanoma cells resistant to apoptosis induced by a MEK inhibitor [2].
  • Only immunoprecipitation followed by immune complex kinase assay or in-gel kinase assay performed against the RSK substrate RRLSSLRA evidenced an increase in p90(rsk) activity (3.4-fold). p90(rsk) was also detected in the GM-CSF-dependent erythroleukemia cell line TF-1 [3].
  • HU-1 was expressed in Epstein-Barr virus lymphocyte > > muscle = liver > fat = placenta [4].
  • SL0101 inhibits proliferation of the human breast cancer cell line MCF-7, producing a cell cycle block in G(1) phase with an efficacy paralleling its ability to inhibit RSK in intact cells [5].

High impact information on RPS6KA1

  • The mammalian target of rapamycin (mTOR) has a central role in the regulation of cell growth. mTOR receives input from multiple signaling pathways, including growth factors and nutrients, to stimulate protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase and eukaryote initiation factor 4E binding protein 1 [6].
  • These studies identify a rapamycin-sensitive signaling pathway, argue for a ubiquitous role for FKBPs in signal transduction, indicate that FK506-FKBP-calcineurin complexes do not interfere with pp70S6K signaling, and show that in fibroblasts pp70S6K, not RSK, is the physiological S6 kinase [7].
  • These findings provide direct evidence that abnormalities in the MAPK/RSK signalling pathway cause Coffin-Lowry syndrome [8].
  • Erk, which is activated by HBX, associates with GSK-3beta through a docking motif ((291)FKFP) of GSK-3beta and phosphorylates GSK-3beta at the (43)Thr residue, which primes GSK-3beta for its subsequent phosphorylation at Ser9 by p90RSK, resulting in inactivation of GSK-3beta and upregulation of beta-catenin [9].
  • The association with Pol I requires phosphorylation of TIF-IA at Ser 649 by RSK kinase, indicating a role for NMI in the growth-dependent regulation of rRNA synthesis [10].

Chemical compound and disease context of RPS6KA1


Biological context of RPS6KA1


Anatomical context of RPS6KA1


Associations of RPS6KA1 with chemical compounds

  • This was supported by findings that hsp60 stimulated phosphorylation of RSK1/2 and cyclic AMP response element-binding protein and increased expression of transcription factors c-Jun and c-Fos [20].
  • RESULTS: We identify here a pro-survival role for the serine/threonine kinase Rsk1, a downstream target of the MEK-MAP kinase signaling pathway [21].
  • Stimulation of these cells with ionomycin also resulted in increased ribosomal S6 kinase activity [22].
  • We conclude that 1) the NH2-terminal RSK kinase domain mediates substrate phosphorylation; 2) both domains contribute to autophosphorylation; 3) the putative MAPK phosphorylation site is not required for growth factor-stimulated autophosphorylation or kinase activation [23].
  • In mouse Hepa1c1c, human HepG2 cells, and rat primary hepatocytes, oltipraz induced phosphorylation of C/EBPbeta at Thr(217), Thr(266), and Ser(105), respectively, via RSK1 [24].

Physical interactions of RPS6KA1


Enzymatic interactions of RPS6KA1


Regulatory relationships of RPS6KA1

  • Consistent with this hypothesis, we find that inactivating mutations in the RSK1 kinase domains disrupted the mitogen-regulated dissociation of ERK1/2 in vivo [30].
  • In addition, overexpression of the dominant inhibitory mutant (S32A/S36A) of IkappaBalpha inhibited PMA-stimulated and RSK1-enhanced megakaryocytic differentiation, indicating that NF-kappaB mediates a signal for megakaryocytic differentiation downstream of RSK1 [16].
  • RSK1 was activated in a time- and dose-dependent manner during the PMA-induced differentiation [16].
  • RSK1 is activated directly by interaction with YopM, and RSK1 kinase activity is required for YopM-stimulated PRK2 activity [31].
  • Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site [32].

Other interactions of RPS6KA1


Analytical, diagnostic and therapeutic context of RPS6KA1


  1. The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation. Clark, D.E., Errington, T.M., Smith, J.A., Frierson, H.F., Weber, M.J., Lannigan, D.A. Cancer Res. (2005) [Pubmed]
  2. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Eisenmann, K.M., VanBrocklin, M.W., Staffend, N.A., Kitchen, S.M., Koo, H.M. Cancer Res. (2003) [Pubmed]
  3. S6 kinase p90rsk in granulocyte-macrophage colony-stimulating factor-stimulated proliferative and mature hematopoietic cells. Joseph, D.E., Paul, C.C., Baumann, M.A., Gomez-Cambronero, J. J. Biol. Chem. (1996) [Pubmed]
  4. Human rsk isoforms: cloning and characterization of tissue-specific expression. Moller, D.E., Xia, C.H., Tang, W., Zhu, A.X., Jakubowski, M. Am. J. Physiol. (1994) [Pubmed]
  5. Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation. Smith, J.A., Poteet-Smith, C.E., Xu, Y., Errington, T.M., Hecht, S.M., Lannigan, D.A. Cancer Res. (2005) [Pubmed]
  6. Dysregulation of the TSC-mTOR pathway in human disease. Inoki, K., Corradetti, M.N., Guan, K.L. Nat. Genet. (2005) [Pubmed]
  7. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Chung, J., Kuo, C.J., Crabtree, G.R., Blenis, J. Cell (1992) [Pubmed]
  8. Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Trivier, E., De Cesare, D., Jacquot, S., Pannetier, S., Zackai, E., Young, I., Mandel, J.L., Sassone-Corsi, P., Hanauer, A. Nature (1996) [Pubmed]
  9. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Ding, Q., Xia, W., Liu, J.C., Yang, J.Y., Lee, D.F., Xia, J., Bartholomeusz, G., Li, Y., Pan, Y., Li, Z., Bargou, R.C., Qin, J., Lai, C.C., Tsai, F.J., Tsai, C.H., Hung, M.C. Mol. Cell (2005) [Pubmed]
  10. Nuclear actin and myosin I are required for RNA polymerase I transcription. Philimonenko, V.V., Zhao, J., Iben, S., Dingová, H., Kyselá, K., Kahle, M., Zentgraf, H., Hofmann, W.A., de Lanerolle, P., Hozák, P., Grummt, I. Nat. Cell Biol. (2004) [Pubmed]
  11. Estradiol prevents the injury-induced decrease of 90 ribosomal S6 kinase (p90RSK) and Bad phosphorylation. Koh, P.O. Neurosci. Lett. (2007) [Pubmed]
  12. Effect of clarithromycin on Pseudomonas aeruginosa biofilms. Tanaka, G., Shigeta, M., Komatsuzawa, H., Sugai, M., Suginaka, H., Usui, T. Chemotherapy. (2000) [Pubmed]
  13. Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Ballif, B.A., Roux, P.P., Gerber, S.A., MacKeigan, J.P., Blenis, J., Gygi, S.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1. Richards, S.A., Dreisbach, V.C., Murphy, L.O., Blenis, J. Mol. Cell. Biol. (2001) [Pubmed]
  15. Leukotriene D4 mediates survival and proliferation via separate but parallel pathways in the human intestinal epithelial cell line Int 407. Paruchuri, S., Sjölander, A. J. Biol. Chem. (2003) [Pubmed]
  16. Extracellular signal-regulated kinase/90-KDA ribosomal S6 kinase/nuclear factor-kappa B pathway mediates phorbol 12-myristate 13-acetate-induced megakaryocytic differentiation of K562 cells. Kim, K.W., Kim, S.H., Lee, E.Y., Kim, N.D., Kang, H.S., Kim, H.D., Chung, B.S., Kang, C.D. J. Biol. Chem. (2001) [Pubmed]
  17. Activation of p90RSK and cAMP response element binding protein in stimulated neutrophils: novel effects of the pyridinyl imidazole SB 203580 on activation of the extracellular signal-regulated kinase cascade. Lian, J.P., Huang, R., Robinson, D., Badwey, J.A. J. Immunol. (1999) [Pubmed]
  18. Nonclassical action of retinoic acid on the activation of the cAMP response element-binding protein in normal human bronchial epithelial cells. Aggarwal, S., Kim, S.W., Cheon, K., Tabassam, F.H., Yoon, J.H., Koo, J.S. Mol. Biol. Cell (2006) [Pubmed]
  19. Intracellular network of phosphatidylinositol 3-kinase, mammalian target of the rapamycin/70 kDa ribosomal S6 kinase 1, and mitogen-activated protein kinases pathways for regulating mycobacteria-induced IL-23 expression in human macrophages. Yang, C.S., Song, C.H., Lee, J.S., Jung, S.B., Oh, J.H., Park, J., Kim, H.J., Park, J.K., Paik, T.H., Jo, E.K. Cell. Microbiol. (2006) [Pubmed]
  20. Bacterial heat shock protein-60 increases epithelial cell proliferation through the ERK1/2 MAP kinases. Zhang, L., Pelech, S.L., Mayrand, D., Grenier, D., Heino, J., Uitto, V.J. Exp. Cell Res. (2001) [Pubmed]
  21. Rsk1 mediates a MEK-MAP kinase cell survival signal. Shimamura, A., Ballif, B.A., Richards, S.A., Blenis, J. Curr. Biol. (2000) [Pubmed]
  22. Activation of MAP2-kinase in B lymphocytes by calcium ionophores. Franklin, R.A., Tordai, A., Mazer, B., Terada, N., Lucas, J.J., Gelfand, E.W. J. Immunol. (1994) [Pubmed]
  23. Divergent functional roles for p90rsk kinase domains. Bjørbaek, C., Zhao, Y., Moller, D.E. J. Biol. Chem. (1995) [Pubmed]
  24. Role of p90 ribosomal S6-kinase-1 in oltipraz-induced specific phosphorylation of CCAAT/enhancer binding protein-beta for GSTA2 gene transactivation. Lee, S.J., Kim, S.G. Mol. Pharmacol. (2006) [Pubmed]
  25. 90-kDa ribosomal S6 kinase is a direct target for the nuclear fibroblast growth factor receptor 1 (FGFR1): role in FGFR1 signaling. Hu, Y., Fang, X., Dunham, S.M., Prada, C., Stachowiak, E.K., Stachowiak, M.K. J. Biol. Chem. (2004) [Pubmed]
  26. Induction of MUC8 gene expression by interleukin-1 beta is mediated by a sequential ERK MAPK/RSK1/CREB cascade pathway in human airway epithelial cells. Song, K.S., Seong, J.K., Chung, K.C., Lee, W.J., Kim, C.H., Cho, K.N., Kang, C.D., Koo, J.S., Yoon, J.H. J. Biol. Chem. (2003) [Pubmed]
  27. Ribosomal S6 kinase-1 modulates interleukin-1beta-induced persistent activation of NF-{kappa}B through phosphorylation of I{kappa}Bbeta. Xu, S., Bayat, H., Hou, X., Jiang, B. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  28. The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaBalpha and stimulates its degradation in vitro. Ghoda, L., Lin, X., Greene, W.C. J. Biol. Chem. (1997) [Pubmed]
  29. T cell receptor activation of a ribosomal S6 kinase activity. Calvo, V., Bierer, B.E., Vik, T.A. Eur. J. Immunol. (1992) [Pubmed]
  30. Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity. Roux, P.P., Richards, S.A., Blenis, J. Mol. Cell. Biol. (2003) [Pubmed]
  31. The yersinia virulence factor YopM forms a novel protein complex with two cellular kinases. McDonald, C., Vacratsis, P.O., Bliska, J.B., Dixon, J.E. J. Biol. Chem. (2003) [Pubmed]
  32. Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site. Woo, M.S., Ohta, Y., Rabinovitz, I., Stossel, T.P., Blenis, J. Mol. Cell. Biol. (2004) [Pubmed]
  33. Cloning and characterization of Xenopus Rsk2, the predominant p90 Rsk isozyme in oocytes and eggs. Bhatt, R.R., Ferrell, J.E. J. Biol. Chem. (2000) [Pubmed]
  34. RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK). Pierrat, B., Correia, J.S., Mary, J.L., Tomás-Zuber, M., Lesslauer, W. J. Biol. Chem. (1998) [Pubmed]
  35. Stimulation of insulin-like growth factor binding protein-1 synthesis by interleukin-1beta: requirement of the mitogen-activated protein kinase pathway. Frost, R.A., Nystrom, G.J., Lang, C.H. Endocrinology (2000) [Pubmed]
  36. p90 RSK-1 associates with and inhibits neuronal nitric oxide synthase. Song, T., Sugimoto, K., Ihara, H., Mizutani, A., Hatano, N., Kume, K., Kambe, T., Yamaguchi, F., Tokuda, M., Watanabe, Y. Biochem. J. (2007) [Pubmed]
  37. Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. Fang, C.X., Yang, X., Sreejayan, N., Ren, J. Exp. Neurol. (2007) [Pubmed]
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