Affinage

RPS6KA4

Ribosomal protein S6 kinase alpha-4 · UniProt O75676

Length
772 aa
Mass
85.6 kDa
Annotated
2026-04-28
20 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPS6KA4 (MSK2) is a dual-kinase-domain nuclear serine/threonine kinase activated downstream of both ERK1/2 and p38 MAPK that functions as a central chromatin and transcription-factor kinase linking mitogen and stress signaling to immediate-early gene expression, inflammatory cytokine regulation, and chromatin remodeling. MSK2, together with the paralog MSK1, is the major kinase responsible for stimulus-induced phosphorylation of histone H3 at Ser10 and Ser28, HMG-14, and the transcription factors CREB (Ser133) and ATF1, thereby driving transcription of c-fos, junB, IL-10, and DUSP1; loss of both MSKs causes hypersensitivity to endotoxic shock owing to defective IL-10-mediated negative feedback on TLR signaling (PMID:12773393, PMID:11909979, PMID:18690222). MSK2 is selectively phosphorylated by CK2 at Ser324 during UV stress, enabling it to phosphorylate NF-κB p65 at Ser276 and activate NF-κB-dependent gene expression, a function not shared by MSK1 (PMID:19933278). Independent of its catalytic activity, MSK2 inhibits p53 transcriptional function by sequestering the coactivator p300 at target promoters such as Noxa; apoptotic stimuli relieve this inhibition through MSK2 degradation (PMID:19797274).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    Identification of MSK2 as a p38α MAPK substrate established it as a dual-kinase-domain nuclear kinase that phosphorylates CREB and activates CRE/AP1-dependent transcription, answering how p38 signaling reaches nuclear transcription-factor targets.

    Evidence Intracellular interaction screen baited with p38α, in vitro kinase assay, reporter assays, and subcellular fractionation in mammalian cells

    PMID:9792677

    Open questions at the time
    • Physiological substrates beyond CREB peptides not yet defined
    • Relative contribution of ERK versus p38 axis unclear
    • No loss-of-function data
  2. 2002 High

    Genetic knockout demonstrated that MSK1/MSK2 are required for stress-induced CREB and ATF1 phosphorylation and for full immediate-early gene (c-fos, junB) induction, resolving which kinases are the physiological CREB Ser133 kinases downstream of MAPK cascades.

    Evidence MSK1/MSK2 single and double knockout mouse embryonic fibroblasts with phosphorylation and transcription readouts

    PMID:11909979

    Open questions at the time
    • Individual contributions of MSK1 versus MSK2 not fully separated
    • Stimulus-specific roles (mitogen vs. stress) not delineated for all targets
  3. 2003 High

    Double-knockout studies established MSK1/MSK2 as the major histone H3 Ser10/Ser28 and HMG-14 kinases in mitogen- and stress-stimulated fibroblasts, linking MAPK signaling directly to chromatin remodeling.

    Evidence MSK1/MSK2 double-knockout mouse fibroblasts with in vivo histone phosphorylation assays across multiple stimuli

    PMID:12773393

    Open questions at the time
    • Locus-specific versus global H3 phosphorylation roles not resolved
    • Functional consequence of H3 phosphorylation on gene transcription not directly tested
  4. 2006 Medium

    ChIP-based promoter analysis showed that MSK1/MSK2 mediate EGF-induced H3 Ser10 phosphorylation at specific gene promoters (c-fos, IκBα) and are required for optimal c-fos transcription, demonstrating locus-specific chromatin kinase function.

    Evidence MSK1/MSK2 knockdown with ChIP and gene expression analysis in stimulated cells

    PMID:16517600

    Open questions at the time
    • TNF-induced H3 phosphorylation uses a different kinase — identity unknown
    • Genome-wide target promoter landscape not mapped
  5. 2008 High

    In vivo knockout studies revealed that MSK1/MSK2 serve as critical anti-inflammatory effectors by inducing IL-10 and DUSP1 via CREB/ATF1 phosphorylation, establishing a negative-feedback loop on TLR signaling that limits endotoxic shock and contact eczema.

    Evidence MSK1/MSK2 double-knockout mice, macrophage LPS stimulation, ChIP on IL-10 and DUSP1 promoters, in vivo endotoxin shock and eczema models

    PMID:18690222

    Open questions at the time
    • Relative individual contributions of MSK1 versus MSK2 to IL-10 induction not separated
    • Downstream transcriptional programs beyond IL-10/DUSP1 not profiled
  6. 2009 High

    Two parallel discoveries established MSK2-specific functions: CK2 phosphorylates MSK2 at Ser324 to enable UV-induced NF-κB p65 Ser276 phosphorylation (distinguishing MSK2 from MSK1), and MSK2 inhibits p53 independently of kinase activity by blocking p300 coactivator function, revealing a non-catalytic adaptor role.

    Evidence Co-IP, S324A mutagenesis, RNAi rescue for CK2–NF-κB axis; Co-IP, kinase-dead mutant, ChIP at Noxa promoter for p53–p300 axis

    PMID:19797274 PMID:19933278

    Open questions at the time
    • Structural basis of MSK2–p300 interaction unknown
    • Whether CK2-dependent activation of MSK2 extends beyond UV stress untested
    • In vivo relevance of p53 inhibition not confirmed with knockout
  7. 2011 Medium

    MSK2 was found to stimulate PKR phosphorylation during HCV replication as an adaptor, independent of its own kinase activity, extending the non-catalytic adaptor paradigm to antiviral signaling.

    Evidence Co-immunoprecipitation and kinase-dead mutant analysis in HCV-replicating cells

    PMID:21385567

    Open questions at the time
    • Mechanism by which MSK2 binding activates PKR not defined
    • Not independently confirmed by another group
    • In vivo relevance during viral infection untested
  8. 2013 Medium

    The MSK-IL-10 axis was extended to post-transcriptional control: MSK1/2-driven IL-10 promotes cox-2 mRNA degradation via p38/MK2/TTP, explaining elevated prostaglandin E2 in MSK-deficient macrophages and broadening the anti-inflammatory reach of MSKs. Separately, NF-κB was shown to transcriptionally induce RPS6KA4 itself, creating a feedforward loop coupling NF-κB activation to p53 suppression.

    Evidence MSK1/2 KO macrophages with mRNA stability and prostaglandin assays; NF-κB inhibitor and dominant-negative experiments with MSK2 knockdown/rescue and apoptosis assays

    PMID:23382072 PMID:23599020

    Open questions at the time
    • Direct NF-κB binding sites in the RPS6KA4 promoter not mapped
    • Relative roles of MSK1 versus MSK2 in cox-2 mRNA regulation unclear
  9. 2016 Medium

    miR-93 was identified as a physiological suppressor of MSK2 in podocytes, linking MSK2-driven H3 Ser10 phosphorylation and chromatin dynamics to diabetic nephropathy pathogenesis.

    Evidence Inducible miR-93 transgenic mice, MSK2 knockdown in podocytes, H3S10 phosphorylation and chromatin remodeling assays, diabetic nephropathy model

    PMID:27350436

    Open questions at the time
    • Target genes affected by MSK2-driven H3S10 phosphorylation in podocytes not identified
    • Whether MSK1 compensates in podocytes not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the genome-wide set of MSK2-specific (versus MSK1-redundant) chromatin and transcription-factor targets; the structural basis of MSK2's non-catalytic interactions with p300 and PKR; and whether MSK2-selective functions identified in vitro (NF-κB p65 phosphorylation, p53 inhibition, PKR activation) are recapitulated with MSK2 single-knockout models in vivo.
  • No MSK2 single-knockout phenotype characterized in vivo for p53/NF-κB/PKR axes
  • No structural model of MSK2–p300 or MSK2–PKR complexes
  • Genome-wide MSK2-specific ChIP-seq targets not available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 4 GO:0042393 histone binding 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ATF1CREB1CSNK2A1EIF2AK2EP300MAPK14RELA

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RPS6KA4 (RSK-B/MSK2) was identified as a substrate of p38α MAPK via an intracellular interaction screen; it is activated by p38αMAPK and more weakly by ERK1, contains two catalytic domains (N-terminal PKC-like and C-terminal CaM kinase-like), phosphorylates CREB and c-Fos peptides, drives CRE- and AP1-dependent reporter expression, and localizes to the cell nucleus where it co-translocates p38αMAPK. p38αMAPK-baited intracellular interaction screen, in vitro kinase assay, reporter gene assay, subcellular localization The Journal of biological chemistry High 9792677
2003 MSK1 and MSK2 are the major kinases responsible for mitogen- and stress-induced phosphorylation of histone H3 (Ser10, Ser28) and HMG-14 in fibroblasts; this was established using MSK1/MSK2 double-knockout mice showing severely reduced or abolished H3 and HMG-14 phosphorylation, while H3 acetylation remained unimpaired. MSK1/MSK2 double-knockout mouse fibroblasts, in vivo phosphorylation assay, immediate-early gene induction assay The EMBO journal High 12773393
2002 MSK1 and MSK2 are required for stress-induced (and partially mitogen-induced) phosphorylation of transcription factors CREB (Ser133) and ATF1 in primary embryonic fibroblasts, and MSK1/MSK2 double knockout reduces c-fos and junB transcription by ~50% in response to stress stimuli. MSK1/MSK2 single and double knockout mouse embryonic fibroblasts, phosphorylation assay, gene expression analysis Molecular and cellular biology High 11909979
2008 MSK1 and MSK2 act as negative regulators of TLR signaling by inducing transcription of DUSP1 and IL-10; they mediate phosphorylation of CREB and ATF1, enabling binding to the promoters of IL-10 and DUSP1 genes. MSK1/2 double-deficient mice show hypersensitivity to LPS-induced endotoxic shock and prolonged contact eczema. MSK1/MSK2 double-knockout mice, macrophage stimulation with LPS, chromatin immunoprecipitation (ChIP), cytokine measurement, in vivo endotoxin shock model Nature immunology High 18690222
2006 MSK1 and MSK2 are required for EGF-induced, but not TNF-induced, histone H3 Ser10 phosphorylation globally and at specific promoters (c-fos, IκBα), and are required for optimal EGF-induced c-fos transcription through control of both H3-Ser10 and CREB phosphorylation. MSK1/MSK2 knockdown, ChIP, in vivo phosphorylation assay, gene expression analysis The Journal of biological chemistry Medium 16517600
2009 CK2 protein kinase physically interacts with MSK2 (but not MSK1) and phosphorylates MSK2 at Ser324; CK2 inhibition or the S324A mutation impairs UV-induced MSK2 kinase activation. MSK2 (but not MSK1) is responsible for UV-induced phosphorylation of NF-κB p65 at Ser276, promoting NF-κB-responsive gene expression. Co-immunoprecipitation, site-directed mutagenesis (S324A), RNAi knockdown, ectopic expression rescue, in vivo phosphorylation assay, reporter gene assay The Journal of biological chemistry High 19933278
2009 MSK2 inhibits p53 transcriptional activity in the absence of stress independently of its kinase activity and upstream MAPK signaling; MSK2 interacts with and inhibits the p53 coactivator p300, associates with the Noxa promoter, and apoptotic stimuli promote MSK2 degradation to relieve p53 inhibition. Co-immunoprecipitation, kinase-dead mutant analysis, ChIP, gene expression analysis, apoptosis assay Science signaling Medium 19797274
2011 MSK2 binds PKR and stimulates PKR phosphorylation in the context of HCV replication, apparently functioning as an adaptor independently of its own catalytic activity; MSK1 and RSK2 do not have this effect. Co-immunoprecipitation, in vivo phosphorylation assay, kinase-dead mutant analysis Biochemical and biophysical research communications Medium 21385567
2013 MSK1 and MSK2 regulate cox-2 mRNA stability via an IL-10 feedback mechanism: MSKs promote IL-10 production, which in turn promotes cox-2 mRNA degradation via p38/MK2 and the mRNA-binding protein TTP; MSK1/2 KO macrophages show elevated prostaglandin E2 and cox-2 protein due to reduced IL-10 and impaired mRNA degradation. MSK1/MSK2 knockout macrophages, IL-10 neutralization, mRNA stability assay, prostaglandin measurement, in vivo LPS model Molecular and cellular biology Medium 23382072
2013 NF-κB plays a crucial role in RPS6KA4 gene expression: TNFα induces RPS6KA4 mRNA via NF-κB, and this is blocked by the NF-κB inhibitor BAY11-7082 or dominant-negative NF-κB; RPS6KA4 in turn inhibits p53 function, and its knockdown enhances α-lipoic acid-induced apoptosis in a p53-dependent manner. NF-κB inhibitor, dominant-negative NF-κB transfection, RPS6KA4 knockdown and restoration, apoptosis assay, microarray Anti-cancer drugs Medium 23599020
2014 MSK1 and MSK2 are the major CREB kinases in LPA-stimulated human fibroblast-like synoviocytes; both MSK1 and MSK2 mediate LPA-induced phosphorylation of CREB at Ser133 downstream of ERK1/2 and p38 MAPK, contributing to IL-8 and MCP-1 secretion. siRNA silencing of MSK1/MSK2, pharmacological inhibitor SB747651A, shRNA knockdown of CREB1, phosphorylation assay, cytokine measurement Biochemical pharmacology Medium 24792438
2016 miR-93 targets Msk2 (RPS6KA4) in podocytes; Msk2 phosphorylates histone H3 at Ser10 (H3S10), and miR-93-mediated suppression of Msk2 reduces H3S10 phosphorylation and nucleosomal dynamics, thereby ameliorating diabetic nephropathy-associated chromatin remodeling. Inducible transgenic miR-93 overexpression in podocytes, MSK2 knockdown, H3S10 phosphorylation assay, chromatin remodeling assay, mouse model of diabetic nephropathy Nature communications Medium 27350436
2019 MSK2 promotes cervical cancer cell proliferation via phosphorylation of PAX8, which leads to suppression of RB phosphorylation and downstream activation of E2F1 and cyclin A2; MSK2 knockdown inhibited PAX8 phosphorylation, reduced E2F1 and cyclin A2 expression, and suppressed proliferation and tumor formation. MSK2 knockdown, western blot for PAX8/RB/E2F1/cyclin A2 phosphorylation, proliferation and tumor formation assays in vivo and in vitro 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 374 11909979
2008 The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nature immunology 270 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 55 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 16 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