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RPS6KA4

Ribosomal protein S6 kinase alpha-4 · UniProt O75676

Length
772 aa
Mass
85.6 kDa
Annotated
2026-06-10
20 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPS6KA4 (MSK2) is a nuclear serine/threonine kinase that operates at the convergence of the p38 and ERK1/2 MAPK cascades to couple mitogenic and stress signaling to chromatin remodeling and immediate-early gene transcription (PMID:9792677, PMID:11909979). It was identified as a CREB kinase activated predominantly downstream of p38α and more weakly by ERK1, phosphorylating CREB and c-Fos and driving CRE- and AP1-dependent transcription (PMID:9792677). Genetic ablation of MSK1/MSK2 established that these kinases are the major effectors of stress- and mitogen-induced phosphorylation of CREB and ATF1 and of the chromatin substrates histone H3 (Ser10) and HMG-14, with consequent control of immediate-early genes such as c-fos and junB in a pathway- and stimulus-specific manner (PMID:11909979, PMID:12773393, PMID:16517600). Through CREB/ATF1-driven induction of DUSP1 and IL-10, MSK2 acts as a negative feedback brake on TLR/LPS-driven inflammation — MSK-deficient macrophages overproduce proinflammatory mediators and the IL-10 loop additionally restrains cox-2 mRNA stability and prostaglandin output, while MSK-deficient mice are hypersensitive to endotoxic shock (PMID:18690222, PMID:23382072). MSK2 is also distinguished from MSK1 by a CK2-dependent activation arm: CK2 binds MSK2 and phosphorylates it at Ser324 to enable UV-induced phosphorylation of NF-κB p65 at Ser276 (PMID:19933278). Beyond its catalytic functions, MSK2 has kinase-independent activities, binding and suppressing the p53 coactivator p300 to restrain p53 transcription in unstressed cells (PMID:19797274).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    Established MSK2 as a MAPK-activated nuclear CREB kinase, defining its position as an effector linking p38/ERK signaling to transcription-factor phosphorylation.

    Evidence p38αMAPK-baited interaction screen, in vitro kinase assays, reporter assays, and localization imaging

    PMID:9792677

    Open questions at the time
    • Endogenous substrate repertoire not defined
    • Relative contribution of p38 vs ERK in vivo not resolved
  2. 2002 High

    Genetic knockouts demonstrated MSK1/MSK2 are the principal kinases for stress-induced CREB/ATF1 phosphorylation and contribute substantially to immediate-early gene induction, moving the model from biochemistry to physiology.

    Evidence MSK1/MSK2 single and double knockout mice, primary fibroblast phospho-immunoblotting, RT-PCR

    PMID:11909979

    Open questions at the time
    • Residual mitogen-induced phosphorylation indicates other kinases contribute
    • Direct vs indirect contribution to gene induction not separated
  3. 2003 High

    Identified histone H3 and HMG-14 as chromatin substrates of MSK1/MSK2, establishing the kinases as a route by which signaling remodels chromatin at induced loci independently of H3 acetylation.

    Evidence MSK1/MSK2 double knockout fibroblasts, phospho-H3/HMG-14 immunoblotting and immunofluorescence, ChIP

    PMID:12773393

    Open questions at the time
    • Functional consequence of H3 phosphorylation for transcription only partially defined
    • Genome-wide target loci not mapped
  4. 2006 High

    Showed that MSK-dependent H3-Ser10 phosphorylation is stimulus- and promoter-specific (EGF but not TNF), refining the model from a global to a pathway-selective chromatin mark.

    Evidence Knockout cells, siRNA, ChIP at specific promoters, promoter-specific H3-Ser10 assays

    PMID:16517600

    Open questions at the time
    • Mechanism of pathway selectivity not defined
    • Promoter recruitment determinants unknown
  5. 2008 High

    Defined MSK1/MSK2 as an anti-inflammatory feedback module that induces DUSP1 and IL-10 to limit cytokine output, explaining the in vivo endotoxin hypersensitivity of MSK-deficient mice.

    Evidence MSK1/MSK2 double knockout macrophages, cytokine ELISA, ChIP for phospho-CREB/ATF1 at promoters, in vivo endotoxin shock model

    PMID:18690222

    Open questions at the time
    • Relative roles of MSK1 vs MSK2 not dissected
    • Other anti-inflammatory targets beyond DUSP1/IL-10 not enumerated
  6. 2009 High

    Distinguished MSK2 from MSK1 by a CK2-Ser324 activation mechanism that drives UV-induced NF-κB p65 Ser276 phosphorylation, identifying a stimulus-specific signaling input unique to MSK2.

    Evidence Co-IP, RNAi, S324A mutagenesis, in vivo phosphorylation and NF-κB reporter assays, CK2 inhibition

    PMID:19933278

    Open questions at the time
    • Structural basis of CK2-MSK2 selectivity unknown
    • Generality beyond UV stimulus not tested
  7. 2009 High

    Revealed a kinase-independent function in which MSK2 binds and suppresses p300 to restrain p53 transcription, with apoptotic MSK2 degradation relieving this brake.

    Evidence Reciprocal Co-IP, kinase-dead mutant, ChIP at Noxa promoter, p53 target expression, degradation assays

    PMID:19797274

    Open questions at the time
    • Structural basis of MSK2-p300 interaction unknown
    • Degradation pathway/E3 ligase not identified
  8. 2011 Medium

    Proposed a second non-catalytic adaptor role in which MSK2 binds PKR to promote its activation during HCV infection, distinct from related kinases.

    Evidence Co-IP, in vitro/in vivo PKR phosphorylation assays, catalytically inactive mutant, comparison with MSK1/RSK2

    PMID:21385567

    Open questions at the time
    • Single lab/single paper
    • Direct vs scaffold-mediated PKR activation not resolved
  9. 2013 High

    Extended the anti-inflammatory feedback model by linking MSK-driven IL-10 to suppression of cox-2 mRNA stability and prostaglandin production via p38/MK2/TTP.

    Evidence MSK1/MSK2 knockout macrophages, IL-10 neutralization/restoration, mRNA stability assays, prostaglandin ELISA, in vivo LPS model

    PMID:23382072

    Open questions at the time
    • Quantitative contribution of this loop to overall inflammation resolution unclear
  10. 2013 Medium

    Placed RPS6KA4 in an NF-κB-driven transcriptional feedback that suppresses p53, with α-lipoic acid acting through NF-κB to downregulate RPS6KA4 and license apoptosis.

    Evidence Microarray, RT-PCR, dominant-negative NF-κB, NF-κB inhibitor, RPS6KA4 rescue, p53-WT vs -deficient comparison

    PMID:23599020

    Open questions at the time
    • Direct MSK2-p53 mechanism not validated here
    • Single lab
  11. 2014 Medium

    Showed MSK1/MSK2 mediate LPA-induced CREB Ser133 phosphorylation and chemokine secretion in synoviocytes, extending the MAPK-MSK-CREB axis to a chemokine output.

    Evidence siRNA of MSK1/MSK2/CREB1, inhibitor SB747651A, phospho-CREB immunoblotting, IL-8/MCP-1 ELISA

    PMID:24792438

    Open questions at the time
    • Direct kinase-substrate validation absent
    • MSK1 vs MSK2 contributions not separated
  12. 2016 Medium

    Linked Msk2-dependent H3S10 phosphorylation to chromatin reorganization in podocytes and identified miR-93 as an upstream regulator in diabetic nephropathy.

    Evidence Podocyte-specific miR-93 transgenic mice, Western blot for Msk2/H3S10, chromatin accessibility assays

    PMID:27350436

    Open questions at the time
    • Direct kinase assay not described
    • miR-93-Msk2 targeting inferred
  13. 2019 Low

    Associated MSK2 with a PAX8/RB-E2F1/cyclin A2 proliferation axis in cervical cancer cells.

    Evidence MSK2 siRNA knockdown, phospho-PAX8/RB and E2F1/cyclin A2 immunoblotting, proliferation and tumor formation assays

    PMID:30756420

    Open questions at the time
    • No direct kinase assay or mutagenesis confirming MSK2-PAX8 as a direct phosphorylation event
    • Single knockdown study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MSK2's catalytic and non-catalytic (p300-suppressing, PKR-adaptor) functions are coordinated, and what determines stimulus- and promoter-specific substrate selection, remains unresolved.
  • No structural model integrating kinase and scaffold roles
  • Determinants of promoter targeting unknown
  • MSK1 vs MSK2 functional divergence incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
CREB1CSNK2A1EIF2AK2EP300MAPK14

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RSK-B (RPS6KA4/MSK2) was identified as a novel CREB kinase activated downstream of p38αMAPK (dominant control) and more weakly by ERK1. It phosphorylates CREB and c-Fos peptides, drives CRE- and AP1-dependent reporter expression in intracellular assays, and localizes to the cell nucleus, co-translocating p38αMAPK. p38αMAPK-baited intracellular interaction screen, in vitro kinase assays, reporter gene assays, subcellular localization imaging The Journal of biological chemistry High 9792677
2002 MSK1 and MSK2 are required for stress-induced phosphorylation of transcription factors CREB and ATF1 in primary embryonic fibroblasts, and doubly required for mitogen-induced CREB/ATF1 phosphorylation (greatly reduced but not abolished). Loss of both MSK1 and MSK2 reduced c-fos and junB transcription by ~50% in response to stress stimuli. MSK1 and MSK2 single and double knockout mice; primary embryonic fibroblast assays; immunoblotting for phospho-CREB/ATF1; RT-PCR for immediate-early gene expression Molecular and cellular biology High 11909979
2003 MSK2 (together with MSK1) is a major kinase responsible for mitogen- and stress-induced phosphorylation of histone H3 and HMG-14 in fibroblasts. Mice lacking both MSK1 and MSK2 show severely reduced or abolished histone H3 and HMG-14 phosphorylation in response to mitogens or stress stimuli. Histone H3 acetylation was unimpaired in these cells, and immediate-early genes could still be induced (though at reduced efficiency), establishing that MSK-mediated H3 phosphorylation is not required for H3 acetylation. MSK1/MSK2 double knockout mice; primary fibroblast assays; immunoblotting and immunofluorescence for phospho-H3 and phospho-HMG-14; chromatin immunoprecipitation The EMBO journal High 12773393
2006 MSK1 and MSK2 are required for EGF-induced, but not TNF-induced, histone H3 Ser10 phosphorylation both globally and at specific promoters. MSK1/2 are also required for optimal EGF-induced c-fos transcription and control EGF-induced IκBα promoter H3-Ser10 phosphorylation, demonstrating pathway-specific mechanisms for H3-Ser10 phosphorylation. MSK1/MSK2 knockout cells; siRNA knockdown; chromatin immunoprecipitation; immunoblotting; promoter-specific H3-Ser10 phosphorylation assays The Journal of biological chemistry High 16517600
2008 MSK1 and MSK2, acting downstream of p38 and ERK1/2 MAPKs, are required to limit proinflammatory cytokine production in LPS-stimulated macrophages. They do so by inducing transcription of DUSP1 and IL-10; MSK-deficient macrophages show impaired CREB and ATF1 binding to DUSP1 and IL-10 promoters. MSK1/MSK2 double-deficient mice are hypersensitive to LPS-induced endotoxic shock. MSK1/MSK2 double knockout mice; primary macrophage assays; ELISA for cytokines; ChIP for phospho-CREB/ATF1 at promoters; in vivo endotoxin shock model Nature immunology High 18690222
2009 CK2 protein kinase physically interacts with MSK2 but not MSK1, and CK2 inhibition specifically impairs UV-induced MSK2 kinase activation. CK2 phosphorylates MSK2 at Ser324; the S324A mutation compromises MSK2 activity. MSK2 (but not MSK1) is the major kinase responsible for UV-induced phosphorylation of NF-κB p65 at Ser276, promoting NF-κB transcriptional activity. Co-immunoprecipitation; RNAi knockdown; site-directed mutagenesis (S324A); in vivo phosphorylation assays; NF-κB reporter assays; CK2 pharmacological inhibition The Journal of biological chemistry High 19933278
2009 MSK2 inhibits p53 transcriptional activity in the absence of stress independently of its kinase activity and independently of upstream MAPK signaling. MSK2 physically interacts with and inhibits the p53 coactivator p300, and associates with the Noxa promoter. Apoptotic stimuli promote MSK2 degradation, thereby relieving p53 inhibition and enabling p53-dependent Noxa transactivation and apoptosis. Co-immunoprecipitation (MSK2-p300 interaction); kinase-dead MSK2 mutant; ChIP at Noxa promoter; p53 target gene expression analysis; apoptotic stimulus-induced MSK2 degradation assays Science signaling High 19797274
2011 MSK2 binds PKR and stimulates PKR phosphorylation in the context of HCV infection, whereas the closely related MSK1 and RSK2 have no such effect. MSK2 functions as an adaptor to mediate PKR activation, apparently independent of its own catalytic activity. Co-immunoprecipitation (MSK2-PKR binding); in vitro and in vivo PKR phosphorylation assays; catalytically inactive MSK2 mutant; comparison with MSK1 and RSK2 Biochemical and biophysical research communications Medium 21385567
2013 MSK1 and MSK2 promote IL-10 production in LPS-stimulated macrophages, which in turn provides negative feedback on cox-2 mRNA stability via a p38/MK2/TTP mechanism. MSK1/2 knockout macrophages show increased cox-2 mRNA stability, elevated cox-2 protein, and elevated prostaglandin secretion, demonstrating a role for MSK1/2 in limiting prostaglandin production through an IL-10 feedback loop. MSK1/MSK2 knockout macrophages; IL-10 neutralization/restoration experiments; mRNA stability assays; ELISA for prostaglandins; in vivo LPS injection model Molecular and cellular biology High 23382072
2013 NF-κB activates RPS6KA4 gene expression, and RPS6KA4 inhibits p53 function (promoting p53 degradation). α-Lipoic acid downregulates RPS6KA4 mRNA via inhibition of NF-κB nuclear translocation, and restoration of RPS6KA4 expression attenuates α-LA-induced apoptosis in a p53-dependent manner. Microarray; RT-PCR; dominant-negative NF-κB transfection; NF-κB inhibitor (BAY11-7082); RPS6KA4 rescue expression; p53 wild-type vs. deficient cell comparison; Western blot Anti-cancer drugs Medium 23599020
2014 Both MSK1 and MSK2 mediate LPA-induced phosphorylation of CREB at Ser133 and secretion of IL-8 and MCP-1 in fibroblast-like synoviocytes, acting downstream of ERK1/2 and p38 MAPK cascades. Silencing of CREB1 reduced LPA-induced chemokine production, placing CREB downstream of MSKs in this pathway. siRNA knockdown of MSK1, MSK2, and CREB1; pharmacological inhibitor SB747651A; immunoblotting for phospho-CREB; ELISA for IL-8 and MCP-1 Biochemical pharmacology Medium 24792438
2016 Msk2 promotes H3S10 phosphorylation (chromatin remodeling) in podocytes under high-glucose conditions. miR-93 targets Msk2 mRNA to reduce Msk2 expression, thereby altering nucleosomal dynamics and chromatin reorganization in diabetic nephropathy. Inducible podocyte-specific miR-93 transgenic mice; Western blot for Msk2 and H3S10 phosphorylation; chromatin accessibility assays; diabetic nephropathy model Nature communications Medium 27350436
2019 MSK2 knockdown inhibited phosphorylation of PAX8 and retinoblastoma protein (RB), suppressed expression of E2F1 and cyclin A2, and inhibited squamous cervical cancer cell proliferation and tumor formation, placing MSK2 upstream of the PAX8/RB-E2F1/cyclin A2 proliferation axis. MSK2 siRNA knockdown; Western blot for phospho-PAX8, phospho-RB, E2F1, cyclin A2; cell proliferation assays; in vivo tumor formation assays Journal of cellular biochemistry Low 30756420

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. The EMBO journal 411 12773393
2002 MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Molecular and cellular biology 375 11909979
2008 The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nature immunology 271 18690222
1998 RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK). The Journal of biological chemistry 141 9792677
2016 miR-93 regulates Msk2-mediated chromatin remodelling in diabetic nephropathy. Nature communications 56 27350436
2003 MSK1 and MSK2 mediate mitogen- and stress-induced phosphorylation of histone H3: a controversy resolved. Science's STKE : signal transduction knowledge environment 54 12915720
2013 MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop. Molecular and cellular biology 35 23382072
2006 The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation. The Journal of biological chemistry 35 16517600
2011 Mice lacking MSK1 and MSK2 show reduced skin tumor development in a two-stage chemical carcinogenesis model. Cancer investigation 33 21314333
2019 Sulforaphene induces apoptosis and inhibits the invasion of esophageal cancer cells through MSK2/CREB/Bcl-2 and cadherin pathway in vivo and in vitro. Cancer cell international 23 31889894
2009 Differential regulation of mitogen- and stress-activated protein kinase-1 and -2 (MSK1 and MSK2) by CK2 following UV radiation. The Journal of biological chemistry 19 19933278
2013 α-Lipoic acid prevents p53 degradation in colon cancer cells by blocking NF-κB induction of RPS6KA4. Anti-cancer drugs 18 23599020
2020 Discovery of a novel dual-target inhibitor against RSK1 and MSK2 to suppress growth of human colon cancer. Oncogene 17 32963350
2019 MSK2 promotes proliferation and tumor formation in squamous cervical cancer via PAX8/RB-E2F1/cyclin A2 axis. Journal of cellular biochemistry 16 30756420
2009 MSK2 inhibits p53 activity in the absence of stress. Science signaling 16 19797274
2014 Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes. Biochemical pharmacology 12 24792438
2018 RPS6KA4/MIR1237 and AURKC promoter regions are differentially methylated in Wilms' tumor. Frontiers in bioscience (Elite edition) 7 28930610
2023 Potentially functional genetic variants in RPS6KA4 and MAP2K5 in the MAPK signaling pathway predict HBV-related hepatocellular carcinoma survival. Molecular carcinogenesis 4 37278562
2011 HCV-induced PKR activation is stimulated by the mitogen- and stress-activated protein kinase MSK2. Biochemical and biophysical research communications 4 21385567
2024 Prim-O-glucosylcimifugin alleviates influenza virus-induced pneumonia in mice by inhibiting the TGF-β1/PI3KCD/MSK2/RELA signalling pathway. Archives of virology 3 39467851

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