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Gene Review

Rps6ka1  -  ribosomal protein S6 kinase, polypeptide A1

Rattus norvegicus

Synonyms: 90 kDa ribosomal protein S6 kinase 1, MAP kinase-activated protein kinase 1a, MAPK-activated protein kinase 1a, MAPKAP kinase 1a, MAPKAPK-1a, ...
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Disease relevance of Rps6ka1

  • Apoptosis induced by 12 hours of anoxia followed by 24 hours' reoxygenation was significantly reduced in cells expressing Ad.DN-RSK (18.6+/-2.0%) compared with Ad.LacZ (29.3+/-5.4%) [1].
  • These findings establish RSK as a putative NHE-1 kinase and potential mediator of increased Na(+)-H+ exchange in hypertension [2].
  • Detailed investigation of ERK and its downstream effector p90RSK, two putative NHE1 kinases, revealed time-dependent activation of both by intracellular acidosis in NRVM [3].

High impact information on Rps6ka1

  • We have previously shown that stretching cardiac myocytes evokes activation of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and 90-kD ribosomal S6 kinase (p90rsk) [4].
  • Expression of constitutively active Rsk1 or Rsk2 in PC12 cells resulted in highly active proteins whose levels of activity did not change either with NGF treatment or after coexpression with MEK1-DD [5].
  • Expression of Rsk1-CA did not lead to activation of the endogenous MAPK pathway, indicating that Rsk1 is sufficient to induce neurite outgrowth and is the only target of MAPK required for this effect [5].
  • Heregulin-dependent activation of PAK65, a component of the stress-activated signaling pathway, ribosomal S6 kinase, and a cyclic AMP (cAMP) response element binding protein (CREB) kinase, identified as p95(RSK2), was also observed [6].
  • To determine whether this 90-kD kinase was p90rsk (RSK), VSMCs were stimulated with 100 nmol/L angiotensin II, and NHE-1 kinase activity was measured by phosphorylation of recombinant NHE-1 (a glutathione S-transferase fusion protein containing amino acids 516 to 815 of the cytoplasmic carboxyl tail) in vitro [2].

Chemical compound and disease context of Rps6ka1

  • While the abundance of Flk-1 is unaffected by hypoxia, the receptor exhibits a higher level of tyrosine phosphorylation, as do downstream signaling kinases, including extracellular signal-regulated protein kinase, p90RSK and STAT3a, demonstrating activation of the VEGF pathway [7].

Biological context of Rps6ka1

  • By contrast, TPA-activated Rsk-1 is not altered in these properties by phosphorylation in vitro with erk2/MAP kinase [8].
  • DNA sequences encoding the rat Rsk-1 S6 kinase (homologous to Xenopus rsk alpha), modified by insertion of a peptide epitope at the polypeptide aminoterminus, were expressed transiently in COS cells [8].
  • Cardiomyocyte apoptosis was significantly reduced after I/R in DN-RSK (0.9+/-0.2%) compared with nontransgenic littermate controls (6.2+/-2.6%) [1].
  • Although downregulation of PKC did not suppress Ang II-induced activation of MAP kinase and RSK, chelating intracellular Ca2+ by BAPTA-AM completely abolished Ang II-induced activation of these kinases [9].
  • In conclusion, our results indicate that activity of ERK in the cytoplasm is important for survival during oxidative stress in hepatocytes and that RSK is activated downstream of ERK [10].

Anatomical context of Rps6ka1


Associations of Rps6ka1 with chemical compounds

  • Downregulation of RSK by small interfering RNA (SiRNA) in VSMCs was found to suppress Ang II-induced activation of NF-kappaB and p65 phosphorylation [13].
  • A new cellular signaling mechanism for angiotensin II activation of NF-kappaB: An IkappaB-independent, RSK-mediated phosphorylation of p65 [13].
  • Immunopurified RSK from Ang II-treated VSMCs phosphorylated recombinant glutathione S-transferase-p65 in vitro [13].
  • In an in vitro assay, purified PP2A(c) dephosphorylated a GST-NHE1 fusion protein containing aa 625-747 of the NHE1 regulatory domain, which had been pre-phosphorylated by recombinant RSK; such dephosphorylation was inhibited by the PP2A-selective phosphatase inhibitor endothall [11].
  • CONCLUSIONS: In summary, RSK is a novel regulator of cardiac NHE1 activity by phosphorylating NHE1 serine 703 and a new pathological mediator of I/R injury in the heart [1].

Regulatory relationships of Rps6ka1


Other interactions of Rps6ka1

  • Insulin treatment markedly stimulated the activity of a novel 31-kDa S6 kinase and the previously described 90-kDa ribosomal S6 kinase encoded by one of the rsk genes (p90rsk) in the 2-month control rats, while the effect was substantially reduced in the diabetic rats [15].
  • Furthermore, inhibition of MEK1/2 by pretreatment of NRVM with two structurally distinct inhibitors, PD98059 (30 microM) or UO126 (3 microM), inhibited the activation of ERK and p90RSK and abolished the stimulation of NHE activity by sustained (3 min) intracellular acidosis [3].
  • Our results demonstrate that the phosphoinositide 3-kinase, p70/p85 ribosomal S6 kinase, extracellular signal-regulated protein kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinase pathways are not involved in the inhibitory effect of insulin on glucocorticoid-stimulated PF2K/Fru-2,6-BPase [16].
  • First, we confirmed that increased phosphorylation of the 40S ribosomal S6 protein (a cellular substrate for both p70(S6K) and the 90 kDa ribosomal S6 kinase) in response to stimulation of ARVM by insulin-like growth factor-1 (300 ng/mL; 10 min) occurs specifically through rapamycin-sensitive activation of p70(S6K) [17].
  • We demonstrated that both hindlimb unloading and denervation produce alterations in the phosphorylation and/or total amount of the 70-kDa ribosomal S6 kinase, eukaryotic initiation factor 2 alpha-subunit, and eukaryotic elongation factor 2 [18].

Analytical, diagnostic and therapeutic context of Rps6ka1

  • Peptide mapping exhibits a single major 32P-peptide in Rsk-1 isolated from unstimulated cells and 10-12 additional 32P peptides after TPA treatment in situ [8].
  • Indications that the conformation of the recombinant Rsk-1 polypeptide is substantially changed after activation by TPA in situ include a retarded mobility of the Rsk-1 polypeptide on SDS-PAGE and the appearance of new 32P-peptides during autophosphorylation in vitro [8].
  • Islet transplantation partially (RSK2) or fully (Akt, p70S6k) normalized these diabetes-induced changes in insulin signaling proteins [19].
  • We assessed the interaction of RSK with CREB or CREB-binding protein by performing co-immunoprecipitation experiments [20].
  • Western blotting demonstrated that calcineurin (CnA), the 70-kDa ribosomal S6 kinase (p70(S6k)), glycogen synthase kinase-3beta (GSK-3beta), and the phosphorylated forms of GSK-3beta and p70(S6k) (p-GSK-3beta(Ser9) and p-p70(S6kThr389)) were regulated differently with aging and between muscle types [21].


  1. Inhibiting p90 ribosomal S6 kinase prevents (Na+)-H+ exchanger-mediated cardiac ischemia-reperfusion injury. Maekawa, N., Abe, J., Shishido, T., Itoh, S., Ding, B., Sharma, V.K., Sheu, S.S., Blaxall, B.C., Berk, B.C. Circulation (2006) [Pubmed]
  2. Angiotensin II stimulates p90rsk in vascular smooth muscle cells. A potential Na(+)-H+ exchanger kinase. Takahashi, E., Abe, J., Berk, B.C. Circ. Res. (1997) [Pubmed]
  3. Stimulation of the plasma membrane Na+/H+ exchanger NHE1 by sustained intracellular acidosis. Evidence for a novel mechanism mediated by the ERK pathway. Haworth, R.S., McCann, C., Snabaitis, A.K., Roberts, N.A., Avkiran, M. J. Biol. Chem. (2003) [Pubmed]
  4. Mechanical stress activates protein kinase cascade of phosphorylation in neonatal rat cardiac myocytes. Yamazaki, T., Komuro, I., Kudoh, S., Zou, Y., Shiojima, I., Mizuno, T., Takano, H., Hiroi, Y., Ueki, K., Tobe, K. J. Clin. Invest. (1995) [Pubmed]
  5. Activation of p90 Rsk1 is sufficient for differentiation of PC12 cells. Silverman, E., Frödin, M., Gammeltoft, S., Maller, J.L. Mol. Cell. Biol. (2004) [Pubmed]
  6. Synergistic regulation of Schwann cell proliferation by heregulin and forskolin. Rahmatullah, M., Schroering, A., Rothblum, K., Stahl, R.C., Urban, B., Carey, D.J. Mol. Cell. Biol. (1998) [Pubmed]
  7. Paracrine and autocrine functions of neuronal vascular endothelial growth factor (VEGF) in the central nervous system. Ogunshola, O.O., Antic, A., Donoghue, M.J., Fan, S.Y., Kim, H., Stewart, W.B., Madri, J.A., Ment, L.R. J. Biol. Chem. (2002) [Pubmed]
  8. Regulation of an epitope-tagged recombinant Rsk-1 S6 kinase by phorbol ester and erk/MAP kinase. Grove, J.R., Price, D.J., Banerjee, P., Balasubramanyam, A., Ahmad, M.F., Avruch, J. Biochemistry (1993) [Pubmed]
  9. Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes. The critical role of Ca(2+)-dependent signaling. Sadoshima, J., Qiu, Z., Morgan, J.P., Izumo, S. Circ. Res. (1995) [Pubmed]
  10. Cytoplasmic retention of peroxide-activated ERK provides survival in primary cultures of rat hepatocytes. Rosseland, C.M., Wierød, L., Oksvold, M.P., Werner, H., Ostvold, A.C., Thoresen, G.H., Paulsen, R.E., Huitfeldt, H.S., Skarpen, E. Hepatology (2005) [Pubmed]
  11. A novel role for protein phosphatase 2A in receptor-mediated regulation of the cardiac sarcolemmal Na+/H+ exchanger NHE1. Snabaitis, A.K., D'Mello, R., Dashnyam, S., Avkiran, M. J. Biol. Chem. (2006) [Pubmed]
  12. Differential localization of MAPK-activated protein kinases RSK1 and MSK1 in mouse brain. Heffron, D., Mandell, J.W. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  13. A new cellular signaling mechanism for angiotensin II activation of NF-kappaB: An IkappaB-independent, RSK-mediated phosphorylation of p65. Zhang, L., Ma, Y., Zhang, J., Cheng, J., Du, J. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  14. Cholecystokinin stimulates a specific ribosomal S6 kinase in rat pancreatic acini. Sung, C.K., Williams, J.A. Pancreas (1990) [Pubmed]
  15. Skeletal muscle mitogen-activated protein kinases and ribosomal S6 kinases. Suppression in chronic diabetic rats and reversal by vanadium. Hei, Y.J., Chen, X., Pelech, S.L., Diamond, J., McNeill, J.H. Diabetes (1995) [Pubmed]
  16. Insulin inhibits glucocorticoid-stimulated L-type 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression by activation of the c-Jun N-terminal kinase pathway. De Los Pinos E, n.u.l.l., Fernández De Mattos S, n.u.l.l., Joaquin, M., Tauler, A. Biochem. J. (2001) [Pubmed]
  17. Specificity of action of bisindolylmaleimide protein kinase C inhibitors: do they inhibit the 70kDa ribosomal S6 kinase in cardiac myocytes? Roberts, N.A., Marber, M.S., Avkiran, M. Biochem. Pharmacol. (2004) [Pubmed]
  18. Regulation of translation factors during hindlimb unloading and denervation of skeletal muscle in rats. Hornberger, T.A., Hunter, R.B., Kandarian, S.C., Esser, K.A. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  19. Effects of streptozocin-induced diabetes and islet cell transplantation on insulin signaling in rat skeletal muscle. Markuns, J.F., Napoli, R., Hirshman, M.F., Davalli, A.M., Cheatham, B., Goodyear, L.J. Endocrinology (1999) [Pubmed]
  20. Extracellular receptor kinase and cAMP response element binding protein activation in the neonatal rat heart after perinatal cocaine exposure. Sun, L.S., Quamina, A. Pediatr. Res. (2004) [Pubmed]
  21. Regulation of p70S6k, GSK-3beta, and calcineurin in rat striated muscle during aging. Kinnard, R.S., Mylabathula, D.B., Uddemarri, S., Rice, K.M., Wright, G.L., Blough, E.R. Biogerontology. (2005) [Pubmed]
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