Gene Symbol: Rps6ka4
Description: ribosomal protein S6 kinase, polypeptide 4
Alias: 1110069D02Rik, 90kDa, AI848992, Msk2, mMSK2, ribosomal protein S6 kinase alpha-4, 90 kDa ribosomal protein S6 kinase 4, RLSK, RSK-like protein kinase, S6K-alpha-4, mitogen- and stress-activated protein kinase-2, nuclear mitogen- and stress-activated protein kinase 2, ribosomal protein S6 kinase, 90kD, polypeptide 4
Species: mouse
Products:     Rps6ka4

Top Publications

  1. Wiggin G, Soloaga A, Foster J, Murray Tait V, Cohen P, Arthur J. MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Mol Cell Biol. 2002;22:2871-81 pubmed
    Using mouse knockouts for mitogen- and stress-activated protein kinase 1 (MSK1) and MSK2 and a double knockout of both MSK1 and MSK2, we show that these protein kinases are required for the stress-induced phosphorylation of transcription ..
  2. Remenyi J, Hunter C, Cole C, Ando H, Impey S, Monk C, et al. Regulation of the miR-212/132 locus by MSK1 and CREB in response to neurotrophins. Biochem J. 2010;428:281-91 pubmed publisher
  3. Ananieva O, Darragh J, Johansen C, Carr J, McIlrath J, Park J, et al. The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol. 2008;9:1028-36 pubmed publisher
    The kinases MSK1 and MSK2 are activated 'downstream' of the p38 and Erk1/2 mitogen-activated protein kinases...
  4. Casanova E, Fehsenfeld S, Greiner E, Stewart A, Schutz G. Construction of a conditional allele of RSK-B/MSK2 in the mouse. Genesis. 2002;32:158-60 pubmed
  5. Naqvi S, Macdonald A, McCoy C, Darragh J, Reith A, Arthur J. Characterization of the cellular action of the MSK inhibitor SB-747651A. Biochem J. 2012;441:347-57 pubmed publisher
    MSK1 (mitogen- and stress-activated kinase 1) and MSK2 are nuclear protein kinases that regulate transcription downstream of the ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38? MAPKs (mitogen-activated protein kinases) via the ..
  6. Darragh J, Ananieva O, Courtney A, Elcombe S, Arthur J. MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages. Biochem J. 2010;425:595-602 pubmed publisher
    ..MSKs therefore act as important negative regulators of inflammation following TLR activation. ..
  7. Arthur J, Fong A, Dwyer J, Davare M, Reese E, Obrietan K, et al. Mitogen- and stress-activated protein kinase 1 mediates cAMP response element-binding protein phosphorylation and activation by neurotrophins. J Neurosci. 2004;24:4324-32 pubmed
    ..These results indicate that MSK1 is the major neurotrophin-activated Ser133 kinase in CNS neurons. ..
  8. Soloaga A, Thomson S, Wiggin G, Rampersaud N, Dyson M, Hazzalin C, et al. MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J. 2003;22:2788-97 pubmed
    ..more, we show that histone H3 and HMG-14 phosphorylation is severely reduced or abolished in mice lacking MSK1 and MSK2. We also show that, despite this, histone H3 acetylation is unimpaired in these cells and that IE genes can be ..
  9. Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J. 2003;22:1313-24 pubmed
    ..This effect represents, together with phosphorylation of nucleosome components such as histone H3, an essential step leading to selective transcriptional activation of NF-kappaB-dependent gene expression. ..

More Information


  1. Cao R, Butcher G, Karelina K, Arthur J, Obrietan K. Mitogen- and stress-activated protein kinase 1 modulates photic entrainment of the suprachiasmatic circadian clock. Eur J Neurosci. 2013;37:130-40 pubmed publisher
    ..Together, these data provide key new insights into the molecular mechanisms by which MSK1 affects the SCN clock. ..
  2. Duncan E, Anest V, Cogswell P, Baldwin A. The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation. J Biol Chem. 2006;281:12521-5 pubmed
    ..These studies demonstrate the existence of pathway-specific mechanisms to control histone H3-Ser10 phosphorylation and gene expression. ..
  3. Lang E, Bissinger R, Fajol A, Salker M, Singh Y, Zelenak C, et al. Accelerated apoptotic death and in vivo turnover of erythrocytes in mice lacking functional mitogen- and stress-activated kinase MSK1/2. Sci Rep. 2015;5:17316 pubmed publisher
    ..The present observations point to accelerated eryptosis and subsequent clearance of erythrocytes leading to enhanced erythrocyte turnover in MSK1/2-deficient mice. ..
  4. Chang S, Iversen L, Kragballe K, Arthur J, Johansen C. Mice lacking MSK1 and MSK2 show reduced skin tumor development in a two-stage chemical carcinogenesis model. Cancer Invest. 2011;29:240-5 pubmed publisher
    ..These data provide in vivo evidence that MSK1/2 signaling represents a novel tumor-promoting axis in skin carcinogenesis. ..
  5. McGuire V, Rosner D, Ananieva O, Ross E, Elcombe S, Naqvi S, et al. Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways. Mol Cell Biol. 2017;37: pubmed
  6. Smerdová L, Šmerdová J, Kabátková M, Kohoutek J, Blažek D, Machala M, et al. Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway. Carcinogenesis. 2014;35:2534-43 pubmed publisher
  7. Karelina K, Liu Y, Alzate Correa D, Wheaton K, Hoyt K, Arthur J, et al. Mitogen and stress-activated kinases 1/2 regulate ischemia-induced hippocampal progenitor cell proliferation and neurogenesis. Neuroscience. 2015;285:292-302 pubmed publisher
    ..Using the endothelin-1 model of ischemia, wild-type (WT) and MSK1(-/-)/MSK2(-/-) (MSK dKO) mice were injected with BrdU and sacrificed 2 days, 4 weeks, or 6 weeks later for the analysis of ..
  8. Bertelsen T, Iversen L, Riis J, Arthur J, Bibby B, Kragballe K, et al. The role of mitogen- and stress-activated protein kinase 1 and 2 in chronic skin inflammation in mice. Exp Dermatol. 2011;20:140-5 pubmed publisher
    ..Our results indicate that MSK1/2 are involved in the activation of feedback mechanisms that dampen oxazolone-induced skin inflammation. ..
  9. Mikkelsen S, Jensen S, Chiliveru S, Melchjorsen J, Julkunen I, Gaestel M, et al. RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1. J Biol Chem. 2009;284:10774-82 pubmed publisher
    ..Thus, activation of p38 MAPK by RIG-I proceeds via a TRAF2-TAK1-dependent pathway, where the enzymatic activity of the kinase plays an essential role. The p38 MAPK in turn stimulates important processes in the innate antiviral response. ..
  10. Bonito Oliva A, Södersten E, Spigolon G, Hu X, Hellysaz A, Falconi A, et al. Differential regulation of the phosphorylation of Trimethyl-lysine27 histone H3 at serine 28 in distinct populations of striatal projection neurons. Neuropharmacology. 2016;107:89-99 pubmed publisher
    ..These results identify H3K27me3S28p as a potential mediator of the effects exerted by amphetamine and haloperidol, and suggest that these drugs may act by re-activating PcG repressed target genes. ..
  11. MacKenzie K, Clark K, Naqvi S, McGuire V, Nöehren G, Kristariyanto Y, et al. PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol. 2013;190:565-77 pubmed publisher
    ..In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE(2) on IL-10 production. ..
  12. CHAVEZ S, McElroy S, Bossert N, De Jonge C, Rodriguez M, Leong D, et al. Comparison of epigenetic mediator expression and function in mouse and human embryonic blastomeres. Hum Mol Genet. 2014;23:4970-84 pubmed publisher
    ..Finally, we determined that reduced expression via morpholino technologies of a single histone-modifying enzyme, Rps6ka4/Msk2, resulted in cleavage-stage arrest as assessed by time-lapse imaging and was associated with aneuploidy ..
  13. Park J, Al Ramahi I, Tan Q, Mollema N, Diaz Garcia J, Gallego Flores T, et al. RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature. 2013;498:325-331 pubmed publisher
    ..Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases. ..
  14. MacKenzie K, Van Den Bosch M, Naqvi S, Elcombe S, McGuire V, Reith A, et al. MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop. Mol Cell Biol. 2013;33:1456-67 pubmed publisher
    Prostaglandin production is catalyzed by cyclooxygenase 2 (cox-2). We demonstrate here that MSK1 and MSK2 (MSK1/2) can exert control on the induction of cox-2 mRNA by Toll-like receptor (TLR) agonists...
  15. Mu M, Koide N, Hassan F, Islam S, Sugiyama T, Ito H, et al. A role of mitogen and stress-activated protein kinase 1/2 in survival of lipopolysaccharide-stimulated RAW 264.7 macrophages. FEMS Immunol Med Microbiol. 2005;43:277-86 pubmed
    ..RAW 264.7 cells transfected with the dominant-negative MSK1 clones underwent cell death in response to LPS. Hence, it was suggested that MSK1/2 might play a critical role in the survival of LPS-stimulated RAW 264.7 cells. ..
  16. Choi Y, Karelina K, Alzate Correa D, Hoyt K, Impey S, Arthur J, et al. Mitogen- and stress-activated kinases regulate progenitor cell proliferation and neuron development in the adult dentate gyrus. J Neurochem. 2012;123:676-88 pubmed publisher
    ..Here, we examined the role of the MAPK-regulated kinases, mitogen- and stress-activated kinase (MSK)1 and MSK2. as regulators of dentate gyrus SGZ progenitor cell proliferation and neurogenesis...
  17. Commodaro A, Bombardieri C, Peron J, Saito K, Guedes P, Hamassaki D, et al. p38{alpha} MAP kinase controls IL-17 synthesis in vogt-koyanagi-harada syndrome and experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 2010;51:3567-74 pubmed publisher
  18. Chandramohan Y, Droste S, Arthur J, Reul J. The forced swimming-induced behavioural immobility response involves histone H3 phospho-acetylation and c-Fos induction in dentate gyrus granule neurons via activation of the N-methyl-D-aspartate/extracellular signal-regulated kinase/mitogen- and str. Eur J Neurosci. 2008;27:2701-13 pubmed publisher
    ..We conclude that the forced swimming-induced behavioural immobility response requires histone H3 phospho-acetylation and c-Fos induction in distinct dentate granule neurons through recruitment of the NMDA/ERK/MSK 1/2 pathway. ..
  19. Deak M, Clifton A, Lucocq L, Alessi D. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998;17:4426-41 pubmed
    ..These findings, together with other observations, suggest that MSK1 may mediate the growth-factor and stress-induced activation of CREB. ..
  20. Wang L, Gordon R, Huynh L, Su X, Park Min K, Han J, et al. Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins. Immunity. 2010;32:518-30 pubmed publisher
    ..These results provide an indirect mechanism of cross-inhibition of TLRs and delineate a signaling pathway important for deactivation of macrophages. ..
  21. Zaru R, Ronkina N, Gaestel M, Arthur J, Watts C. The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways. Nat Immunol. 2007;8:1227-35 pubmed
    ..Thus, in DCs, p38 contributes to the activation of all known MK families. ..
  22. Badal S, Wang Y, Long J, Corcoran D, CHANG B, Truong L, et al. miR-93 regulates Msk2-mediated chromatin remodelling in diabetic nephropathy. Nat Commun. 2016;7:12076 pubmed publisher
    ..miR-93 has a critical role in chromatin reorganization and progression of DN by modulating its target Msk2, a histone kinase, and its substrate H3S10...
  23. Bhat N, Park J, Zoghbi H, Arthur J, Zaret K. The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development. PLoS ONE. 2016;11:e0166703 pubmed publisher
    ..investigate the temporal dynamics of ser-28 phosphorylated histone H3 (H3S28ph) and its upstream kinases, MSK1 and MSK2 (MSK1/2). H3S28ph and MSK1/2 were enriched at the key endocrine and acinar promoters in E12...
  24. Elcombe S, Naqvi S, Van Den Bosch M, MacKenzie K, Cianfanelli F, Brown G, et al. Dectin-1 regulates IL-10 production via a MSK1/2 and CREB dependent pathway and promotes the induction of regulatory macrophage markers. PLoS ONE. 2013;8:e60086 pubmed publisher
    ..The expression of these makers was further reinforced by the high level of IL-10 secreted in response to zymosan stimulation. ..
  25. Remenyi J, Van Den Bosch M, Palygin O, Mistry R, McKenzie C, Macdonald A, et al. miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity. PLoS ONE. 2013;8:e62509 pubmed publisher
  26. McGuire V, Gray A, Monk C, Santos S, Lee K, Aubareda A, et al. Cross talk between the Akt and p38? pathways in macrophages downstream of Toll-like receptor signaling. Mol Cell Biol. 2013;33:4152-65 pubmed publisher
    ..These data describe a novel role for p38?-MK2/3 in regulating TLR-induced Akt activation in macrophages. ..
  27. Naqvi S, Martin K, Arthur J. CREB phosphorylation at Ser133 regulates transcription via distinct mechanisms downstream of cAMP and MAPK signalling. Biochem J. 2014;458:469-79 pubmed publisher
    ..Despite this, MSK-mediated CREB phosphorylation is critical for the induction of CREB-dependent genes downstream of MAPK signalling. ..
  28. Kurita H, Schnekenburger M, Ovesen J, Xia Y, Puga A. The Ah receptor recruits IKK? to its target binding motifs to phosphorylate serine-10 in histone H3 required for transcriptional activation. Toxicol Sci. 2014;139:121-32 pubmed publisher
    ..IKK?), mitogen and stress activated protein kinase 1 (MSK1), and mitogen and stress activated protein kinase 2 (MSK2), whose binding to the Cyp1a1 enhancer was significantly increased by TCDD in Hepa-1c1c7 cells and absent in ..
  29. Kaiser M, Wiggin G, Lightfoot K, Arthur J, Macdonald A. MSK regulate TCR-induced CREB phosphorylation but not immediate early gene transcription. Eur J Immunol. 2007;37:2583-95 pubmed
    ..This correlated to a reduction in the TCR-induced up-regulation of the IL-2 receptor CD25 and a requirement for MSK in IL-2-induced CREB phosphorylation. ..