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Gene Review

RPS6KA5  -  ribosomal protein S6 kinase, 90kDa,...

Homo sapiens

Synonyms: 90 kDa ribosomal protein S6 kinase 5, MSK1, MSPK1, Nuclear mitogen-and stress-activated protein kinase 1, RLPK, ...
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Disease relevance of RPS6KA5


High impact information on RPS6KA5

  • Here we report that PKA, MAPK, and MSK1, a CREB kinase, are coactivated in a subset of hippocampal CA1 pyramidal neurons following contextual fear conditioning [6].
  • We show that the mitogen-activated protein kinase inhibitors SB203580 and PD98059 or U0126, as well as a potent mitogen- and stress- activated protein kinase-1 (MSK1) inhibitor H89, counteract tumor necrosis factor (TNF)-mediated stimulation of p65 transactivation capacity [7].
  • The loss of phosphorylation is not due to changes in cell cycle distribution and/or apoptosis and is mediated independent of either p46/54(JNK) or MSK-1/2 inhibition [8].
  • The levels of phospho-H3 and MSK1 associated with the TFF1 promoter were moderately increased [9].
  • In the presence of TPA, whereas ERalpha was not bound to the promoter, a strong association of acetylated and/or phospho-H3, MSK1, and c-Jun was observed [9].

Biological context of RPS6KA5


Anatomical context of RPS6KA5


Associations of RPS6KA5 with chemical compounds

  • We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1 [15].
  • Phosphorylation by MSK1 induced an increase in Vmax and a decrease in Km for 6-(R)-5,6,7,8-tetrahydrobiopterin (BH4), while these kinetic parameters were unaffected as a result of phosphorylation by PRAK [16].
  • In parallel, we observed that all three subfamilies of the mitogen-activated protein kinases (MAPKs) attained their maximal phosphorylation levels at 5-15min of H(2)O(2) treatment, with mitogen- and stress-activated-protein kinase 1 (MSK1) also being maximally phosphorylated at 15min [17].
  • Moreover, the inhibition of the p38 MAPK downstream effector MSK1 with the specific inhibitor H89, or the overexpression of a kinase defective MSK1 abrogated the NFkappaB-dependent transcription induced by cholesterol depletion [18].
  • Following this approach, we have identified octahedral ruthenium complexes as potent inhibitors for the protein kinases Pim1, MSK1, and GSK3alpha [19].

Physical interactions of RPS6KA5

  • Moreover, we observed that expression of dominant-interfering mutants of MSK1 blocked the binding of Smad3 to the coactivator p300 in response to TGF-beta signaling [20].
  • Consistently, MSK1 interacts with two homologous coactivators of ER81, CBP and p300, and stimulates the transactivation domains of CBP [21].

Enzymatic interactions of RPS6KA5


Regulatory relationships of RPS6KA5

  • Recombinant human tyrosine hydroxylase (hTH1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (MSK1) at Ser40 and by p38 regulated/activated kinase (PRAK) on Ser19 [16].
  • Furthermore, MSK1/2 control EGF-induced IkappaBalpha promoter H3-Ser(10) phosphorylation in the absence of elevated transcription [22].
  • MSK1 expression enhances ER81-dependent transcription upon stimulation of especially the p38-MAPK pathway [21].

Other interactions of RPS6KA5

  • Furthermore, MNK1 and PRAK1, but not MSK1, is present in platelets and undergo modest activation in response to thrombin [23].
  • MSK2 activity was low, relative to MSK1, with little activation post-exercise [24].
  • Evidence for a role of MSK1 in transforming growth factor-beta-mediated responses through p38alpha and Smad signaling pathways [20].
  • Furthermore, co- immunoprecipitation experiments revealed a potential intracellular signaling complex consisting of ATF2 and ERKs and/or MSK1 [25].
  • ERK1/2 and p38 MAPK phosphorylation and MSK1 activity increased (P < 0.05) after exercise 2.6-, 2.1- and 2.0-fold, respectively, in control subjects and 1.5-, 1.6- and 1.4-fold, respectively, in trained subjects [26].

Analytical, diagnostic and therapeutic context of RPS6KA5


  1. Mitogen- and stress-activated protein kinase 1 is critical for interleukin-1-induced, CREB-mediated, c-fos gene expression in keratinocytes. Schiller, M., Böhm, M., Dennler, S., Ehrchen, J.M., Mauviel, A. Oncogene (2006) [Pubmed]
  2. Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factor-kappaB gene expression by soy isoflavones does not require estrogenic activity. Vanden Berghe, W., Dijsselbloem, N., Vermeulen, L., Ndlovu, N., Boone, E., Haegeman, G. Cancer Res. (2006) [Pubmed]
  3. Activation of JNK1, RSK2, and MSK1 is involved in serine 112 phosphorylation of Bad by ultraviolet B radiation. She, Q.B., Ma, W.Y., Zhong, S., Dong, Z. J. Biol. Chem. (2002) [Pubmed]
  4. Mitogen- and stress-activated protein kinase 1 is activated in lesional psoriatic epidermis and regulates the expression of pro-inflammatory cytokines. Funding, A.T., Johansen, C., Kragballe, K., Otkjaer, K., Jensen, U.B., Madsen, M.W., Fjording, M.S., Finnemann, J., Skak-Nielsen, T., Paludan, S.R., Iversen, L. J. Invest. Dermatol. (2006) [Pubmed]
  5. Activation of the mitogen- and stress-activated kinase 1 by arsenic trioxide. Kannan-Thulasiraman, P., Katsoulidis, E., Tallman, M.S., Arthur, J.S., Platanias, L.C. J. Biol. Chem. (2006) [Pubmed]
  6. Ca(2+)-Stimulated Adenylyl Cyclases Regulate ERK-Dependent Activation of MSK1 during Fear Conditioning. Sindreu, C.B., Scheiner, Z.S., Storm, D.R. Neuron (2007) [Pubmed]
  7. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). Vermeulen, L., De Wilde, G., Van Damme, P., Vanden Berghe, W., Haegeman, G. EMBO J. (2003) [Pubmed]
  8. Selective repression of low-density lipoprotein receptor expression by SP600125: coupling of histone H3-Ser10 phosphorylation and Sp1 occupancy. Huang, W., Batra, S., Korrapati, S., Mishra, V., Mehta, K.D. Mol. Cell. Biol. (2006) [Pubmed]
  9. Chromatin modification of the trefoil factor 1 gene in human breast cancer cells by the Ras/mitogen-activated protein kinase pathway. Espino, P.S., Li, L., He, S., Yu, J., Davie, J.R. Cancer Res. (2006) [Pubmed]
  10. Assignment of a member of the ribosomal protein S6 kinase family, RPS6KA5, to human chromosome 14q31-->q32.1 by radiation hybrid mapping. Jiang, C., Yu, L., Tu, Q., Zhao, Y., Zhang, H., Zhao, S. Cytogenet. Cell Genet. (1999) [Pubmed]
  11. Cloning and characterization of RLPK, a novel RSK-related protein kinase. New, L., Zhao, M., Li, Y., Bassett, W.W., Feng, Y., Ludwig, S., Padova, F.D., Gram, H., Han, J. J. Biol. Chem. (1999) [Pubmed]
  12. The Ras-MAPK signal transduction pathway, cancer and chromatin remodeling. Dunn, K.L., Espino, P.S., Drobic, B., He, S., Davie, J.R. Biochem. Cell Biol. (2005) [Pubmed]
  13. Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism. Butcher, G.Q., Lee, B., Cheng, H.Y., Obrietan, K. J. Neurosci. (2005) [Pubmed]
  14. Tumor necrosis factor activates CRE-binding protein through a p38 MAPK/MSK1 signaling pathway in endothelial cells. Gustin, J.A., Pincheira, R., Mayo, L.D., Ozes, O.N., Kessler, K.M., Baerwald, M.R., Korgaonkar, C.K., Donner, D.B. Am. J. Physiol., Cell Physiol. (2004) [Pubmed]
  15. Phosphorylation of histone H2A inhibits transcription on chromatin templates. Zhang, Y., Griffin, K., Mondal, N., Parvin, J.D. J. Biol. Chem. (2004) [Pubmed]
  16. Regulation of tyrosine hydroxylase by stress-activated protein kinases. Toska, K., Kleppe, R., Armstrong, C.G., Morrice, N.A., Cohen, P., Haavik, J. J. Neurochem. (2002) [Pubmed]
  17. Involvement of JNKs and p38-MAPK/MSK1 pathways in H(2)O(2)-induced upregulation of heme oxygenase-1 mRNA in H9c2 cells. Aggeli, I.K., Gaitanaki, C., Beis, I. Cell. Signal. (2006) [Pubmed]
  18. Low cell cholesterol levels increase NFkappaB activity through a p38 MAPK-dependent mechanism. Calleros, L., Lasa, M., Toro, M.J., Chiloeches, A. Cell. Signal. (2006) [Pubmed]
  19. Rapid access to unexplored chemical space by ligand scanning around a ruthenium center: discovery of potent and selective protein kinase inhibitors. Bregman, H., Carroll, P.J., Meggers, E. J. Am. Chem. Soc. (2006) [Pubmed]
  20. Evidence for a role of MSK1 in transforming growth factor-beta-mediated responses through p38alpha and Smad signaling pathways. Abécassis, L., Rogier, E., Vazquez, A., Atfi, A., Bourgeade, M.F. J. Biol. Chem. (2004) [Pubmed]
  21. Regulation of the ER81 transcription factor and its coactivators by mitogen- and stress-activated protein kinase 1 (MSK1). Janknecht, R. Oncogene (2003) [Pubmed]
  22. The Kinases MSK1 and MSK2 Are Required for Epidermal Growth Factor-induced, but Not Tumor Necrosis Factor-induced, Histone H3 Ser10 Phosphorylation. Duncan, E.A., Anest, V., Cogswell, P., Baldwin, A.S. J. Biol. Chem. (2006) [Pubmed]
  23. Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases. Hefner, Y., Borsch-Haubold, A.G., Murakami, M., Wilde, J.I., Pasquet, S., Schieltz, D., Ghomashchi, F., Yates, J.R., Armstrong, C.G., Paterson, A., Cohen, P., Fukunaga, R., Hunter, T., Kudo, I., Watson, S.P., Gelb, M.H. J. Biol. Chem. (2000) [Pubmed]
  24. Marathon running increases ERK1/2 and p38 MAP kinase signalling to downstream targets in human skeletal muscle. Yu, M., Blomstrand, E., Chibalin, A.V., Krook, A., Zierath, J.R. J. Physiol. (Lond.) (2001) [Pubmed]
  25. Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC-induced phosphorylation of ATF2 in JB6 cells. Zhu, F., Zhang, Y., Bode, A.M., Dong, Z. Carcinogenesis (2004) [Pubmed]
  26. Metabolic and mitogenic signal transduction in human skeletal muscle after intense cycling exercise. Yu, M., Stepto, N.K., Chibalin, A.V., Fryer, L.G., Carling, D., Krook, A., Hawley, J.A., Zierath, J.R. J. Physiol. (Lond.) (2003) [Pubmed]
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