{"gene":"RPS6KA5","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":1998,"finding":"MSK1 (RPS6KA5) is a nuclear serine/threonine kinase containing two kinase domains in a single polypeptide that is directly activated in vitro by ERK2 (MAPK/ERK) and SAPK2/p38, and phosphorylates CREB at Ser133 with a Km far lower than PKA, MAPKAP-K1, or MAPKAP-K2. Growth factor/phorbol ester-induced activation requires the MAPK/ERK cascade (blocked by PD 98059), while stress-induced activation requires SAPK2/p38 (blocked by SB 203580). MSK1 is localized in the nucleus of both unstimulated and stimulated cells.","method":"In vitro kinase assay, pharmacological inhibitor experiments in 293/HeLa/PC12/SK-N-MC cells, subcellular localization, mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay demonstrating activation by ERK2/p38, substrate phosphorylation with Km measurement, inhibitor epistasis in multiple cell lines; seminal founding paper widely replicated","pmids":["9687510"],"is_preprint":false},{"year":1999,"finding":"MSK1 is proposed as the major kinase mediating the nucleosomal response (histone H3 Ser10 and HMG-14 phosphorylation) downstream of both ERK and p38 MAPK pathways: it efficiently phosphorylates H3 and HMG-14 at physiologically relevant sites, and its activity toward these substrates is uniquely sensitive to H89 inhibition, which selectively inhibits the nucleosomal response in intact cells without affecting MAPK activation.","method":"In vitro kinase assay, pharmacological inhibition (H89) in intact cells, immunoblot with phospho-specific antibodies","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay + cell-based pharmacology; genetic confirmation came later (PMID:12773393); single lab at this stage","pmids":["10469656"],"is_preprint":false},{"year":2000,"finding":"MSK1 is required for mitogen-induced phosphorylation of CREB at Ser133 and ATF1 at Ser63 in mouse embryonic stem cells; MSK1-knockout ES cells show abolished TPA- and EGF-induced CREB/ATF1 phosphorylation while basal and PKA-driven (forskolin) phosphorylation remains intact.","method":"MSK1 gene-disruption (knockout) in mouse ES cells, phospho-specific immunoblotting","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with specific phosphorylation readout, distinguishing MSK1-dependent from PKA-dependent CREB phosphorylation; confirmed by subsequent double-KO studies","pmids":["11018520"],"is_preprint":false},{"year":2001,"finding":"MSK1 mediates UVB-induced phosphorylation of histone H3 at Ser28 in vivo; H89 (a selective MSK1 inhibitor) blocks this phosphorylation without affecting MAP kinases; MSK1 phosphorylates Ser28 on histone H3 and chromatin in vitro; dominant-negative N- or C-terminal kinase-dead MSK1 mutants block UVB-induced H3-Ser28 phosphorylation in cells.","method":"In vitro kinase assay, pharmacological inhibition (H89), dominant-negative MSK1 transfection, phospho-specific immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay + mutagenesis (kinase-dead mutants) + cell-based pharmacology, multiple orthogonal methods in one study","pmids":["11441012"],"is_preprint":false},{"year":2001,"finding":"MSK1 phosphorylates STAT3 at Ser727 in vitro and in vivo following UVA irradiation; active MSK1 (but not ERKs or p38) directly phosphorylates STAT3 Ser727 in vitro; kinase-dead MSK1 mutants and H89 suppress UVA-induced Ser727 phosphorylation in cells.","method":"In vitro kinase assay, dominant-negative/kinase-dead mutant transfection, pharmacological inhibition (H89), immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay showing MSK1 phosphorylates STAT3 Ser727, supported by kinase-dead mutants in cells; single lab but multiple orthogonal methods","pmids":["11553624"],"is_preprint":false},{"year":2002,"finding":"MSK1 and MSK2 are required for stress- and mitogen-induced phosphorylation of CREB (Ser133) and ATF1 in primary mouse embryonic fibroblasts; double-knockout of MSK1 and MSK2 results in ~50% reduction in c-fos and junB transcription in response to stress stimuli but minimal reduction in response to mitogens.","method":"MSK1/MSK2 single and double knockout mouse-derived fibroblasts, phospho-specific immunoblotting, gene expression assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO (single and double knockout), multiple phosphorylation and transcription readouts, replicated independently","pmids":["11909979"],"is_preprint":false},{"year":2002,"finding":"MSK1 phosphorylates Bad at Ser112 in vitro and is required for UVB-induced Bad Ser112 phosphorylation in vivo; cells expressing kinase-dead N- or C-terminal MSK1 mutants are defective for UVB-induced Bad phosphorylation; phosphorylation at Ser112 promotes dissociation of Bad from Bcl-XL.","method":"In vitro kinase assay, dominant-negative (kinase-dead) MSK1 mutant transfection, immunoblot with phospho-specific antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay + kinase-dead mutants in cells, multiple orthogonal methods; single lab","pmids":["11983683"],"is_preprint":false},{"year":2003,"finding":"MSK1 and MSK2 are the major kinases mediating mitogen- and stress-induced phosphorylation of histone H3 and HMG-14 in fibroblasts; MSK1/MSK2 double-knockout mouse embryonic fibroblasts show severely reduced or abolished H3 and HMG-14 phosphorylation; H3 acetylation is unimpaired, and immediate-early genes can still be induced but at reduced efficiency.","method":"MSK1/MSK2 double-knockout mice, phospho-specific immunoblotting, immediate-early gene expression assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic double-KO with specific phosphorylation and transcription readouts; resolved prior controversy; widely replicated","pmids":["12773393"],"is_preprint":false},{"year":2003,"finding":"MSK1 associates with NF-κB p65 in a stimulus-dependent manner and phosphorylates p65 at Ser276 in the nucleus; this phosphorylation is required for TNF-induced NF-κB transactivation; mutational analysis identifies Ser276 as the MSK1 target on p65.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of p65, reporter gene assays, pharmacological inhibition","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP + in vitro kinase assay + mutagenesis + reporter assays; replicated in multiple subsequent studies","pmids":["12628924"],"is_preprint":false},{"year":2003,"finding":"MSK1 is required for full c-fos promoter activation and CREB phosphorylation in response to lysophosphatidic acid (LPA) in mouse ES cells, acting downstream of the ERK pathway.","method":"MSK1-knockout ES cells, promoter-reporter assay, phospho-specific immunoblotting","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with functional reporter readout; single lab, two orthogonal methods","pmids":["12769834"],"is_preprint":false},{"year":2003,"finding":"MSK1 phosphorylates and activates the transcription factor ER81; MSK1 targets two serine residues on ER81 and enhances ER81-dependent transcription, particularly downstream of p38-MAPK. MSK1 also interacts with co-activators CBP and p300 and stimulates the transactivation domain of CBP.","method":"In vitro kinase assay, mutagenesis of ER81 phosphorylation sites, reporter gene assay, Co-IP with CBP/p300","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay + mutagenesis + Co-IP; single lab","pmids":["12569367"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of the N-terminal kinase domain of MSK1 (1.8 Å resolution) reveals a unique inactive conformation in which the ATP-binding site is blocked by the nucleotide binding loop, stabilized by a novel three-stranded β-sheet formed by the N terminus, what would be the αB helix, and the activation loop.","method":"X-ray crystallography","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure, direct structural determination of the autoinhibitory conformation","pmids":["15274926"],"is_preprint":false},{"year":2004,"finding":"MSK1 is required for TGF-β-induced transcriptional responses via the p38α/MSK1 pathway; dominant-interfering MSK1 mutants block Smad3 binding to the co-activator p300 in response to TGF-β, positioning MSK1 as a chromatin-remodeling node integrating Smad and p38 MAPK signaling.","method":"Dominant-interfering MSK1 mutants, p38 pharmacological inhibition, Co-IP (Smad3–p300 interaction), transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative mutants + Co-IP + reporter assays; single lab","pmids":["15133024"],"is_preprint":false},{"year":2005,"finding":"MSK1 activity is regulated by a multi-site phosphorylation cascade: ERK1/2 or p38 phosphorylate Thr581 and Ser360, activating the C-terminal kinase domain, which autophosphorylates Ser212 (N-terminal T-loop) and Ser376 (hydrophobic motif), both essential for N-terminal kinase domain activity. Ser381 autophosphorylation also supports activity. Activation does not require PDK1, distinguishing MSK1 from RSKs.","method":"In vitro kinase assay, alanine-scanning mutagenesis of phosphorylation sites, mass spectrometry, activity assays in cells","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of ≥6 phosphorylation sites combined with in vitro kinase assays; multiple orthogonal methods in one study","pmids":["15568999"],"is_preprint":false},{"year":2005,"finding":"In the suprachiasmatic nucleus (SCN), photic stimulation activates MSK1 via a PACAP-ERK/MAPK-dependent mechanism; MSK1 Ser360 phosphorylation (required for kinase activation) is induced by light during the subjective night; activated ERK and MSK1 co-localize in SCN cell nuclei; MSK1 couples to mPeriod1 clock gene expression via a CREB-dependent mechanism.","method":"In vivo phospho-specific immunohistochemistry, MEK inhibitor (U0126) infusion, PACAP receptor antagonist, luciferase reporter assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological epistasis + reporter assay; single lab","pmids":["15930378"],"is_preprint":false},{"year":2007,"finding":"MSK1 has a novel phosphorylation site at Thr700 phosphorylated by upstream kinases ERK1/2 and p38α; mutation of Thr700 increases basal MSK1 activity but dramatically reduces Thr581 phosphorylation (essential for activity), consistent with a mechanism whereby Thr700 phosphorylation relieves inhibition by a C-terminal autoinhibitory helix and induces a conformational shift that protects Thr581 from dephosphorylation.","method":"Precursor ion scanning mass spectrometry, site-directed mutagenesis, in vitro kinase assays, phospho-specific immunoblotting","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS identification of novel phosphorylation sites + systematic mutagenesis + in vitro kinase assay; multiple orthogonal methods; single lab","pmids":["17117922"],"is_preprint":false},{"year":2007,"finding":"MSK1 is the major kinase for Ca2+-ionophore-induced Bad phosphorylation in PC12 cells and cortical neurons; siRNA knockdown of MSK1 reduces Bad phosphorylation; in contrast, knockdown of RSK2 potentiates Bad phosphorylation and elevates ERK phosphorylation, implicating RSK2 in negative-feedback regulation of ERK.","method":"siRNA knockdown of MSK1 or RSK2, phospho-specific immunoblotting in PC12 cells and primary cortical neurons","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific siRNA knockdown in two cell types with defined phosphorylation readout; single lab","pmids":["17663748"],"is_preprint":false},{"year":2007,"finding":"Ca2+-stimulated adenylyl cyclase activity is absolutely required for activation of PKA, MAPK, MSK1, and CREB in hippocampal CA1 pyramidal neurons following contextual fear conditioning; MSK1 is identified as the major CREB kinase activated during training for contextual memory.","method":"Fear-conditioning behavioral paradigm, adenylyl cyclase knockout mice, phospho-specific immunohistochemistry","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model (adenylyl cyclase KO) with specific signaling readouts; single lab","pmids":["17196532"],"is_preprint":false},{"year":2008,"finding":"MSK1 and MSK2 are required to limit pro-inflammatory cytokine production in macrophages stimulated with LPS by inducing transcription of the MAPK phosphatase DUSP1 and anti-inflammatory cytokine IL-10; MSK1/2 deficiency prevents binding of phosphorylated CREB and ATF1 to the DUSP1 and IL-10 gene promoters; MSK1/2 double-knockout mice are hypersensitive to LPS-induced endotoxic shock.","method":"MSK1/MSK2 double-knockout mice and macrophages, cytokine ELISA, chromatin immunoprecipitation (ChIP), endotoxic shock model, contact eczema model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO + ChIP + in vivo disease models; multiple orthogonal methods across multiple biological contexts","pmids":["18690222"],"is_preprint":false},{"year":2008,"finding":"Glucocorticoid receptor (GR), upon ligand activation, triggers redistribution of nuclear MSK1 to the cytoplasm via a CRM1-dependent nuclear export mechanism, mediated by a direct protein-protein interaction between liganded GR and activated MSK1; this altered subcellular distribution reduces MSK1 recruitment to inflammatory gene promoters, thereby inhibiting NF-κB p65 transactivation and histone H3 phosphorylation.","method":"Co-immunoprecipitation (GR–MSK1 interaction), CRM1 inhibitor (leptomycin B), chromatin immunoprecipitation, subcellular fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct protein interaction + CRM1 inhibitor epistasis + ChIP; multiple orthogonal methods in one study","pmids":["18511904"],"is_preprint":false},{"year":2008,"finding":"MSK1 phosphorylates RARα at Ser369 in the ligand-binding domain in a p38MAPK-dependent manner; this phosphorylation allows TFIIH binding and subsequent cdk7/cyclin H-mediated phosphorylation of the RARα N-terminal domain at Ser77; MSK1 also phosphorylates histone H3 at Ser10 in this context; the entire p38MAPK/MSK1-initiated cascade controls recruitment of RARα/TFIIH to response elements and target gene activation.","method":"In vitro kinase assay, site-directed mutagenesis of RARα phosphorylation sites, chromatin immunoprecipitation, pharmacological inhibition of p38MAPK/MSK1","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + ChIP; multiple orthogonal methods in one study; single lab","pmids":["19078967"],"is_preprint":false},{"year":2009,"finding":"MSK1 mediates NF-κB p65 Ser276 phosphorylation induced by p38/ERK MAPK pathways; MSK1 knockdown by siRNA or kinase-dead MSK1 reduces RSV-induced phospho-Ser276 RelA formation; a RelA Ser276Ala mutation abolishes RSV-induced NF-κB-dependent gene expression, establishing that ROS → MSK1 → RelA-Ser276 phosphorylation is a distinct pathway from the pathway controlling RelA cytoplasmic release.","method":"siRNA knockdown of MSK1, pharmacological inhibition (H89), expression of RelA Ser276Ala mutant in RelA-/- MEFs, phospho-specific immunoblotting","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — siRNA + pharmacological inhibition + site mutant reconstitution; multiple orthogonal methods; single lab","pmids":["19706715"],"is_preprint":false},{"year":2009,"finding":"MSK1 is recruited to inflammatory gene promoters as part of a multi-protein complex containing 14-3-3 phospho-serine adaptor proteins and BRG1 (ATPase subunit of SWI/SNF); MSK1 is recruited by transcription factors such as Elk-1 or NF-κB; following MSK1-mediated H3 Ser10/Ser28 phosphorylation, BRG1 associates with promoters via 14-3-3 scaffolds and SWI/SNF remodels nucleosomes to enable transcription factor binding and transcription onset.","method":"Sequential co-immunoprecipitation, sequential chromatin immunoprecipitation (ChIP), MSK1 knockdown cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequential co-IP and sequential ChIP; single lab, two orthogonal methods","pmids":["20129940"],"is_preprint":false},{"year":2010,"finding":"MSK1 phosphorylates histone H3 at the c-fos promoter in a CREB-dependent manner; in a reconstituted cell-free system, activators (SRF, Elk-1, CREB, ATF1) bound to their cognate sites recruit MSK1 to phosphorylate H3 Ser10 within chromatin; CREB plays the predominant role, and Ser133 phosphorylation of CREB is essential; the MSK1 N-terminal inhibition domain is critical for chromatin-embedded H3 phosphorylation.","method":"Cell-free chromatin reconstitution assay, MSK1 mutagenesis (N-terminal inhibition domain), phospho-specific analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro chromatin system + MSK1 mutagenesis; rigorous mechanistic dissection; single lab","pmids":["20089855"],"is_preprint":false},{"year":2010,"finding":"MSK1 is required for induction of the miR-212/132 cluster in primary cortical neurons in response to BDNF; regulation occurs via the ERK1/2 pathway through both MSK-dependent and MSK-independent mechanisms, as shown using MSK1/2 knockout mice and specific inhibitors.","method":"MSK1/2 knockout mice, specific kinase inhibitors, deep sequencing, promoter analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO + inhibitor experiments + promoter analysis; single lab","pmids":["20307261"],"is_preprint":false},{"year":2011,"finding":"An acute psychological stressor induces ERK1/2 phosphorylation in dentate gyrus granule neurons within 15 min, leading to nuclear activation of MSK1 and Elk-1; MSK1 and Elk-1 then evoke H3 Ser10 phosphorylation and H3 Lys14 acetylation, resulting in c-Fos and Egr-1 induction; pERK1/2-mediated activation of MSK1 and Elk-1 requires a direct protein-protein interaction between pERK1/2 and activated glucocorticoid receptors.","method":"In vivo mouse stress model, co-immunoprecipitation (pERK1/2–GR interaction), phospho-specific immunohistochemistry, ChIP","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo phospho-imaging; single lab","pmids":["21808001"],"is_preprint":false},{"year":2012,"finding":"MSK1 is necessary for homeostatic synaptic scaling and experience-dependent synaptic plasticity; neurons from MSK1 kinase-dead knock-in mice fail to show scaling in response to activity deprivation; MSK1 forms part of a BDNF/MAPK-dependent signaling cascade that regulates cell-surface GluA1 expression via induction of Arc/Arg3.1.","method":"MSK1 kinase-dead knock-in mice, electrophysiology (synaptic scaling), rescue by WT MSK1 re-expression, GluA1 surface expression assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinase-dead knock-in + rescue experiment + electrophysiology + molecular readout; multiple orthogonal methods","pmids":["22993422"],"is_preprint":false},{"year":2013,"finding":"Downregulation of RAS-MAPK-MSK1 pathway components decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice; pharmacological inhibition of pathway components also decreases ATXN1 levels, identifying MSK1 as a node in a genetic network that controls the abundance of the SCA1-causing protein.","method":"Parallel cell-based and Drosophila genetic screens, mouse SCA1 model, pharmacological inhibitors, protein level measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screen validated in Drosophila and mouse models with pharmacological confirmation; multiple orthogonal approaches across organisms","pmids":["23719381"],"is_preprint":false},{"year":2016,"finding":"MSK1 (Msk1/RPS6KA5) physically interacts with the KMT2A/MLL1 lysine methyltransferase complex by co-immunoprecipitation; the majority of genes regulated by KMT2A/MLL1 knockdown respond comparably to MSK1 knockdown; KMT2A/MLL1 is required for genomic targeting of MSK1 (but not vice versa); MSK1 supports H3K4 methylation by KMT2A/MLL1 by catalyzing H3S10 and H3S28 phosphorylation.","method":"Co-immunoprecipitation (native and FLAG-tagged), siRNA knockdown, ChIP for H3K4me and H3S10ph at target loci","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP + functional knockdown + ChIP; single lab","pmids":["27895715"],"is_preprint":false},{"year":2016,"finding":"MSK1 phosphorylates β-catenin and regulates its nuclear translocation and transcriptional activity in glioblastoma cells; MSK1 is induced after PI3K/mTOR inhibitor treatment; depletion of MSK1 attenuates resistance to PI3K/mTOR inhibitors; MSK1 inhibition plus PI3K/mTOR inhibition synergizes to extend survival in an intracranial animal model.","method":"shRNA-mediated MSK1 depletion, phospho-specific immunoblotting of β-catenin Ser552, nuclear fractionation, intracranial mouse model","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown + phospho-specific readout + in vivo model; single lab","pmids":["27196759"],"is_preprint":false},{"year":2018,"finding":"MSK1 controls expression of luminal differentiation genes GATA3 and FOXA1 by modulating their promoter chromatin status (H3 phosphorylation); MSK1 downregulation impairs breast cancer cell differentiation, increasing bone homing and growth capacities; in vivo genome-wide shRNA screen identified MSK1 as a regulator of metastatic dormancy.","method":"In vivo genome-wide shRNA screen, MSK1 knockdown/overexpression, ChIP for histone modifications at GATA3/FOXA1 promoters, in vivo bone metastasis model","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide in vivo screen + ChIP + in vivo metastasis model + chromatin mechanism; multiple orthogonal methods","pmids":["29358704"],"is_preprint":false},{"year":2019,"finding":"MSK1 is a downstream target of both early and late ERK activation following DNA damage; early ERK→MSK1 activation (mediated by EGFR) promotes cell survival and DNA repair; late ERK→MSK1 activation (requiring PKCδ) drives apoptosis via a nuclear PKCδ→ERK→MSK1 signaling module; both ERK and MSK1 activations are required for apoptosis in the late phase.","method":"shRNA-mediated depletion of MSK1, PKCδ, and EGFR; pharmacological inhibitors (MEK/ERK, EGFR); phospho-specific immunoblotting; in vivo irradiation model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown + pharmacological inhibition + in vivo validation; single lab, multiple orthogonal methods","pmids":["30679314"],"is_preprint":false},{"year":2020,"finding":"STAT3 aberrantly transactivates MSK1 gene expression, and MSK1 in turn phosphorylates H3S10 and STAT3 itself; STAT3 forms a functional complex with MSK1 at the NFATc2 promoter to promote its transcription in an H3S10 phosphorylation-dependent manner, creating a positive STAT3-MSK1 feedback loop in gastric carcinogenesis.","method":"Co-immunoprecipitation (STAT3–MSK1 complex), ChIP at NFATc2 promoter, MSK1 knockdown/overexpression, xenograft tumor model, phospho-specific immunoblotting","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ChIP + KO/OE with defined readouts; single lab","pmids":["32041943"],"is_preprint":false},{"year":2023,"finding":"MSK1 is transcriptionally activated by HOXC6 in pancreatic ductal adenocarcinoma; MSK1 phosphorylates DDX17 to suppress apoptosis; pharmacological inhibition of MSK1 combined with mTOR inhibition potently suppresses PDAC tumor growth and metastasis in mouse models.","method":"ChIP (HOXC6 at MSK1 promoter), siRNA/shRNA knockdown, phospho-specific identification of DDX17 as MSK1 substrate, in vivo PDAC mouse models, pharmacological inhibition","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + genetic knockdown + in vivo model; single lab; substrate identification requires further validation","pmids":["37951219"],"is_preprint":false},{"year":2017,"finding":"MSK1 regulates BDNF-induced Arc/Arg3.1 expression via phosphorylation of histone H3 at the Arc/Arg3.1 promoter, acting downstream of ERK1/2; however, CREB Ser133 phosphorylation by MSK1 is not required for BDNF-induced Arc/Arg3.1 transcription, as a Ser133Ala CREB knock-in had no effect on induction.","method":"MSK1 kinase-dead knock-in mice, ChIP for H3 phosphorylation at Arc promoter, CREB Ser133Ala knock-in mice, pharmacological inhibitors","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead knock-in + CREB knock-in + ChIP; single lab; CREB negative result is directly tested","pmids":["28593137"],"is_preprint":false},{"year":2009,"finding":"Glucocorticoid-activated GR physically interacts with activated MSK1 (Co-IP) and drives CRM1-dependent nuclear export of MSK1; this redistribution prevents recruitment of activated MSK1 to inflammatory gene promoters (ChIP), resulting in reduced NF-κB p65 transactivation and histone H3 phosphorylation.","method":"Co-immunoprecipitation, CRM1 inhibitor (leptomycin B), ChIP, subcellular fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP + CRM1 pharmacological inhibition + ChIP; multiple orthogonal methods; mechanistically novel","pmids":["18511904"],"is_preprint":false},{"year":2005,"finding":"In NIH 3T3 cells, cAMP/forskolin activates p38 in a PKA-dependent fashion; p38 then activates CREB-mediated transcription via MSK1, as shown using dominant-negative MSK1 mutants and H89, but not dominant-negative MSK2 or MAPKAPK2.","method":"Dominant-negative mutant transfection, pharmacological inhibitors, reporter gene assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative mutants + pharmacological inhibition + reporter assay; single lab","pmids":["16125054"],"is_preprint":false},{"year":2009,"finding":"MSK1 is required for TLR-mediated induction of IL-1ra mRNA and protein from both proximal and distal promoters in macrophages; this occurs via p38 and ERK1/2 MAPK cascades, through both IL-10-dependent and IL-10-independent mechanisms; MSK1/2 knockout mice show decreased IL-1ra production after LPS injection.","method":"MSK1/2 knockout macrophages and mice, RT-PCR/ELISA for IL-1ra, promoter-reporter assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vitro and in vivo + promoter analysis; single lab","pmids":["19922413"],"is_preprint":false},{"year":2005,"finding":"MSK1 is confined to the nucleus of all expressing cell types in mouse brain (neurons and astroglia), in contrast to RSK1 which localizes to the Golgi apparatus; MSK1 is expressed at highest levels in striatal and olfactory tubercle neurons and in cerebellar Purkinje cells, with lower expression in a subset of astroglia.","method":"Immunohistochemistry on adult mouse brain sections","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunolocalization establishing nuclear confinement; replicated across multiple brain regions and cell types; single lab","pmids":["15893597"],"is_preprint":false}],"current_model":"MSK1 (RPS6KA5) is a nuclear serine/threonine kinase with tandem kinase domains that is directly activated by ERK1/2 or p38 MAPK phosphorylation of Thr581/Thr700 on its C-terminal kinase domain, which then autophosphorylates Ser212 and Ser376 to activate the N-terminal catalytic domain; once active, MSK1 phosphorylates multiple nuclear substrates including CREB (Ser133), ATF1, NF-κB p65 (Ser276), histone H3 (Ser10 and Ser28), HMG-14/HMGN1, RARα, STAT3 (Ser727), Bad (Ser112), and β-catenin, coupling mitogenic and stress signals to chromatin remodeling and transcriptional activation of immediate-early genes, anti-inflammatory mediators (IL-10, DUSP1, IL-1ra), and synaptic plasticity genes; glucocorticoid receptor activation can redistribute MSK1 from nucleus to cytoplasm via CRM1-dependent export, and MSK1 physically associates with the KMT2A/MLL1 methyltransferase complex and the SWI/SNF remodeler through 14-3-3 scaffolds to coordinate chromatin opening at target promoters."},"narrative":{"mechanistic_narrative":"RPS6KA5 (MSK1) is a nuclear serine/threonine kinase that couples the ERK1/2 and p38 MAPK cascades to chromatin remodeling and transcription, serving as a terminal effector that converts mitogenic and stress signals into immediate-early gene induction, inflammatory control, and synaptic plasticity [PMID:9687510, PMID:11909979, PMID:12773393]. It is built from two kinase domains in a single polypeptide and is activated by a multi-site phosphorylation cascade: ERK1/2 or p38 phosphorylate the C-terminal kinase domain (Thr581, Ser360, and Thr700), which then autophosphorylates the N-terminal catalytic domain (Ser212, Ser376), with the N-terminal domain held in an autoinhibited conformation by an intramolecular β-sheet seen crystallographically and relieved through this cascade independently of PDK1 [PMID:15274926, PMID:15568999, PMID:17117922]. Once active, MSK1 phosphorylates CREB (Ser133) and ATF1 to drive c-fos and other immediate-early genes [PMID:9687510, PMID:11018520, PMID:11909979], and phosphorylates histone H3 (Ser10, Ser28) and HMGN1/HMG-14 to execute the nucleosomal response [PMID:10469656, PMID:11441012, PMID:12773393]. MSK1 is recruited to target promoters by transcription factors such as Elk-1, CREB, and NF-κB, where its histone phosphorylation creates 14-3-3 docking sites that enable BRG1/SWI/SNF nucleosome remodeling and supports H3K4 methylation by the KMT2A/MLL1 complex with which it associates [PMID:20129940, PMID:20089855, PMID:27895715]. Through phosphorylation of NF-κB p65 (Ser276) and induction of DUSP1, IL-10, and IL-1ra, MSK1 limits pro-inflammatory cytokine output, and MSK1/2-deficient mice are hypersensitive to endotoxic shock [PMID:12628924, PMID:18690222, PMID:19922413]. The kinase additionally phosphorylates STAT3 (Ser727), Bad (Ser112), RARα, ER81, and β-catenin, linking it to apoptosis, nuclear receptor signaling, and oncogenic transcription [PMID:11553624, PMID:11983683, PMID:12569367, PMID:19078967, PMID:27196759]. In neurons, MSK1 is the major CREB kinase for contextual fear memory and mediates BDNF-driven Arc/Arg3.1 and miR-212/132 induction underlying synaptic scaling and plasticity [PMID:17196532, PMID:20307261, PMID:22993422]. Glucocorticoid receptor binding to activated MSK1 drives its CRM1-dependent nuclear export, removing it from inflammatory promoters as an anti-inflammatory mechanism [PMID:18511904].","teleology":[{"year":1998,"claim":"Established the founding identity of MSK1 as a dual-kinase-domain nuclear enzyme directly activated by both ERK and p38 and acting as a high-affinity CREB kinase, defining it as a convergence point for mitogenic and stress signaling.","evidence":"In vitro kinase assays, inhibitor epistasis (PD98059, SB203580), and localization across multiple cell lines","pmids":["9687510"],"confidence":"High","gaps":["In vitro substrate preference does not establish the full in vivo substrate set","Activation mechanism of the tandem kinase domains not yet resolved"]},{"year":1999,"claim":"Proposed MSK1 as the kinase executing the nucleosomal response by phosphorylating histone H3 Ser10 and HMG-14 downstream of both MAPK arms, linking signaling to chromatin.","evidence":"In vitro kinase assay plus H89-based pharmacology in intact cells","pmids":["10469656"],"confidence":"Medium","gaps":["H89 is not fully selective; genetic confirmation was needed","Single lab at this stage"]},{"year":2000,"claim":"Provided genetic proof that MSK1 is required for mitogen-induced CREB/ATF1 phosphorylation, separating MSK1-dependent from PKA-dependent CREB activation.","evidence":"MSK1 gene-disruption in mouse ES cells with phospho-specific immunoblotting","pmids":["11018520"],"confidence":"High","gaps":["Possible MSK2 compensation not addressed in single knockout","Downstream transcriptional consequences not quantified here"]},{"year":2001,"claim":"Extended the MSK1 substrate repertoire to histone H3 Ser28, STAT3 Ser727, and apoptotic regulation, showing direct phosphorylation in vitro and dependence in cells via kinase-dead mutants.","evidence":"In vitro kinase assays, kinase-dead/dominant-negative MSK1 mutants, H89, UV-irradiation cell models","pmids":["11441012","11553624"],"confidence":"High","gaps":["Physiological stimuli beyond UV irradiation not tested for each substrate","Single-lab findings at this stage"]},{"year":2002,"claim":"Double-knockout studies established MSK1/MSK2 as the major kinases for stress-induced CREB/ATF1 and identified Bad Ser112 as a substrate, defining MSK1's role in immediate-early gene transcription and apoptotic gating.","evidence":"MSK1/MSK2 single and double knockout fibroblasts, in vitro kinase assay, gene expression and phospho readouts","pmids":["11909979","11983683"],"confidence":"High","gaps":["Mitogen-induced transcription was only modestly affected, leaving redundant pathways unexplained","Bad phosphorylation was tested mainly under UVB stress"]},{"year":2003,"claim":"Defined MSK1 as the dominant in vivo H3/HMG-14 kinase and a direct NF-κB p65 Ser276 kinase, embedding it in inflammatory transcription, and broadened its targets to ER81 and the TGF-β/Smad axis.","evidence":"MSK1/MSK2 double-knockout mice, reciprocal Co-IP, in vitro kinase assays, mutagenesis, reporter assays","pmids":["12773393","12628924","12569367","12769834"],"confidence":"High","gaps":["How MSK1 is selectively recruited to specific promoters not yet defined","ER81/CBP-p300 and Smad3-p300 links rest on single-lab data"]},{"year":2005,"claim":"Resolved the activation mechanism, defining the ordered multi-site phosphorylation cascade (Thr581/Ser360 → autophosphorylation of Ser212/Ser376) that is PDK1-independent, distinguishing MSK1 from RSKs.","evidence":"Alanine-scanning mutagenesis of ≥6 sites, mass spectrometry, in vitro and cellular kinase assays; with a parallel crystal structure of the autoinhibited N-terminal domain","pmids":["15568999","15274926"],"confidence":"High","gaps":["Full-length active-state structure not determined","Dynamics of inter-domain communication not directly visualized"]},{"year":2005,"claim":"Placed MSK1 in physiological neuronal and cAMP-driven contexts, showing photic activation in the SCN clock circuit and a PKA→p38→MSK1 route to CREB transcription, and confirmed strict nuclear confinement in brain.","evidence":"In vivo phospho-IHC, MEK/PACAP-receptor pharmacology, dominant-negative mutants, reporter assays, brain immunolocalization","pmids":["15930378","16125054","15893597"],"confidence":"Medium","gaps":["In vivo epistasis relies on pharmacology rather than genetics","Single-lab observations"]},{"year":2007,"claim":"Refined activation by identifying Thr700 as an upstream-phosphorylated regulatory site controlling Thr581 stability, and confirmed MSK1 as the major Ca2+-induced Bad kinase and CREB kinase for contextual memory.","evidence":"Precursor-ion-scanning MS, mutagenesis, in vitro kinase assays, siRNA knockdown, adenylyl cyclase knockout mice, fear conditioning","pmids":["17117922","17663748","17196532"],"confidence":"Medium","gaps":["Proposed C-terminal autoinhibitory helix mechanism inferred indirectly","Behavioral causality of MSK1 not isolated from broader cAMP signaling"]},{"year":2008,"claim":"Demonstrated that MSK1/2 enforce anti-inflammatory feedback by inducing DUSP1 and IL-10 via promoter-bound phospho-CREB/ATF1, and uncovered GR-driven CRM1-dependent nuclear export as a mechanism to silence MSK1 at inflammatory promoters.","evidence":"MSK1/MSK2 knockout mice and macrophages, ChIP, cytokine ELISA, endotoxic shock model; Co-IP, leptomycin B, subcellular fractionation","pmids":["18690222","18511904"],"confidence":"High","gaps":["Direct GR-MSK1 interface not mapped","Promoter selectivity of MSK1 recruitment incompletely defined"]},{"year":2009,"claim":"Mechanistically connected MSK1 to chromatin remodeling and nuclear receptor licensing: H3 phosphorylation recruits 14-3-3/BRG1-SWI/SNF, and RARα Ser369 phosphorylation enables TFIIH recruitment, while validating p65 Ser276 as a distinct ROS-driven NF-κB pathway.","evidence":"Sequential Co-IP and ChIP, in vitro kinase assays, RARα/RelA site mutants, siRNA, knockout mice (IL-1ra)","pmids":["20129940","19078967","19706715","19922413","18511904"],"confidence":"Medium","gaps":["Order and stoichiometry of the 14-3-3/SWI-SNF complex assembly not fully resolved","Several findings from single labs"]},{"year":2012,"claim":"Established a reconstituted mechanism for activator-directed H3 phosphorylation at c-fos and defined MSK1's requirement for synaptic scaling, BDNF-driven Arc and miR-212/132 induction, embedding it in plasticity.","evidence":"Cell-free chromatin reconstitution, MSK1 kinase-dead knock-in mice with rescue, electrophysiology, ChIP, deep sequencing","pmids":["20089855","22993422","20307261","28593137"],"confidence":"High","gaps":["Arc induction was shown to be CREB-Ser133-independent, indicating undefined alternative MSK1 outputs","Causal chain from H3 phosphorylation to GluA1 surface expression not fully traced"]},{"year":2023,"claim":"Positioned MSK1 as a disease-relevant transcriptional node controlling protein abundance and tumor behavior, including SCA1-causing ATXN1 levels, breast cancer metastatic dormancy via GATA3/FOXA1, and growth/survival in glioblastoma, gastric, and pancreatic cancers.","evidence":"Drosophila and mouse genetic screens, in vivo genome-wide shRNA screen, ChIP, shRNA depletion, phospho-substrate identification, xenograft/intracranial/PDAC models, pharmacological inhibition","pmids":["23719381","29358704","27196759","32041943","37951219"],"confidence":"Medium","gaps":["β-catenin Ser552 and DDX17 as direct MSK1 substrates rest on single studies","Therapeutic combinations validated only in preclinical models"]},{"year":null,"claim":"How MSK1 achieves promoter and substrate selectivity among its many nuclear targets across distinct physiological contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length active-state structure explaining substrate discrimination","Rules governing context-specific recruitment (transcription factor vs chromatin) not defined","Human disease-causing mutations in RPS6KA5 not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5,8,20,29]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,3,7,23]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,18,30]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,38]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19,35]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,5,7,30]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,7,22,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,18,37]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[17,24,26]}],"complexes":["KMT2A/MLL1 methyltransferase complex","SWI/SNF (BRG1) remodeling complex"],"partners":["CREB","NF-KB P65 (RELA)","STAT3","GR (NR3C1)","14-3-3","BRG1 (SMARCA4)","KMT2A","CBP/P300"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75582","full_name":"Ribosomal protein S6 kinase alpha-5","aliases":["90 kDa ribosomal protein S6 kinase 5","Nuclear mitogen- and stress-activated protein kinase 1","RSK-like protein kinase","RSKL"],"length_aa":802,"mass_kda":89.9,"function":"Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes (PubMed:11909979, PubMed:12569367, PubMed:12763138, PubMed:18511904, PubMed:9687510, PubMed:9873047). Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin (PubMed:11909979, PubMed:9873047). Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression (PubMed:12628924, PubMed:18511904). In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress (PubMed:12628924). In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential (PubMed:12763138). Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation (PubMed:12569367). Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A (PubMed:15010469). Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN (PubMed:12773393). May also phosphorylate 'Ser-28' of histone H3 (PubMed:12773393). Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14) (PubMed:12773393). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines (By similarity). Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors (By similarity). Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury (By similarity). Phosphorylates TRIM7 at 'Ser-107' in response to growth factor signaling via the MEK/ERK pathway, thereby stimulating its ubiquitin ligase activity (PubMed:25851810)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O75582/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RPS6KA5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RPS6KA5","total_profiled":1310},"omim":[{"mim_id":"613786","title":"MICRO RNA 148A; MIR148A","url":"https://www.omim.org/entry/613786"},{"mim_id":"608360","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 8A; LRRC8A","url":"https://www.omim.org/entry/608360"},{"mim_id":"603607","title":"RIBOSOMAL PROTEIN S6 KINASE A5; RPS6KA5","url":"https://www.omim.org/entry/603607"},{"mim_id":"602810","title":"HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER A; HIST1H3A","url":"https://www.omim.org/entry/602810"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPS6KA5"},"hgnc":{"alias_symbol":["MSK1","RLPK"],"prev_symbol":[]},"alphafold":{"accession":"O75582","domains":[{"cath_id":"1.10.510.10","chopping":"33-355_370-377","consensus_level":"medium","plddt":77.6493,"start":33,"end":377},{"cath_id":"3.30.200.20","chopping":"404-498","consensus_level":"high","plddt":81.1892,"start":404,"end":498},{"cath_id":"1.10.510.10","chopping":"504-727","consensus_level":"high","plddt":75.627,"start":504,"end":727}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75582","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75582-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75582-F1-predicted_aligned_error_v6.png","plddt_mean":69.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPS6KA5","jax_strain_url":"https://www.jax.org/strain/search?query=RPS6KA5"},"sequence":{"accession":"O75582","fasta_url":"https://rest.uniprot.org/uniprotkb/O75582.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75582/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75582"}},"corpus_meta":[{"pmid":"9687510","id":"PMC_9687510","title":"Mitogen- 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Growth factor/phorbol ester-induced activation requires the MAPK/ERK cascade (blocked by PD 98059), while stress-induced activation requires SAPK2/p38 (blocked by SB 203580). MSK1 is localized in the nucleus of both unstimulated and stimulated cells.\",\n      \"method\": \"In vitro kinase assay, pharmacological inhibitor experiments in 293/HeLa/PC12/SK-N-MC cells, subcellular localization, mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay demonstrating activation by ERK2/p38, substrate phosphorylation with Km measurement, inhibitor epistasis in multiple cell lines; seminal founding paper widely replicated\",\n      \"pmids\": [\"9687510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MSK1 is proposed as the major kinase mediating the nucleosomal response (histone H3 Ser10 and HMG-14 phosphorylation) downstream of both ERK and p38 MAPK pathways: it efficiently phosphorylates H3 and HMG-14 at physiologically relevant sites, and its activity toward these substrates is uniquely sensitive to H89 inhibition, which selectively inhibits the nucleosomal response in intact cells without affecting MAPK activation.\",\n      \"method\": \"In vitro kinase assay, pharmacological inhibition (H89) in intact cells, immunoblot with phospho-specific antibodies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay + cell-based pharmacology; genetic confirmation came later (PMID:12773393); single lab at this stage\",\n      \"pmids\": [\"10469656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MSK1 is required for mitogen-induced phosphorylation of CREB at Ser133 and ATF1 at Ser63 in mouse embryonic stem cells; MSK1-knockout ES cells show abolished TPA- and EGF-induced CREB/ATF1 phosphorylation while basal and PKA-driven (forskolin) phosphorylation remains intact.\",\n      \"method\": \"MSK1 gene-disruption (knockout) in mouse ES cells, phospho-specific immunoblotting\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with specific phosphorylation readout, distinguishing MSK1-dependent from PKA-dependent CREB phosphorylation; confirmed by subsequent double-KO studies\",\n      \"pmids\": [\"11018520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MSK1 mediates UVB-induced phosphorylation of histone H3 at Ser28 in vivo; H89 (a selective MSK1 inhibitor) blocks this phosphorylation without affecting MAP kinases; MSK1 phosphorylates Ser28 on histone H3 and chromatin in vitro; dominant-negative N- or C-terminal kinase-dead MSK1 mutants block UVB-induced H3-Ser28 phosphorylation in cells.\",\n      \"method\": \"In vitro kinase assay, pharmacological inhibition (H89), dominant-negative MSK1 transfection, phospho-specific immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay + mutagenesis (kinase-dead mutants) + cell-based pharmacology, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11441012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MSK1 phosphorylates STAT3 at Ser727 in vitro and in vivo following UVA irradiation; active MSK1 (but not ERKs or p38) directly phosphorylates STAT3 Ser727 in vitro; kinase-dead MSK1 mutants and H89 suppress UVA-induced Ser727 phosphorylation in cells.\",\n      \"method\": \"In vitro kinase assay, dominant-negative/kinase-dead mutant transfection, pharmacological inhibition (H89), immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay showing MSK1 phosphorylates STAT3 Ser727, supported by kinase-dead mutants in cells; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11553624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MSK1 and MSK2 are required for stress- and mitogen-induced phosphorylation of CREB (Ser133) and ATF1 in primary mouse embryonic fibroblasts; double-knockout of MSK1 and MSK2 results in ~50% reduction in c-fos and junB transcription in response to stress stimuli but minimal reduction in response to mitogens.\",\n      \"method\": \"MSK1/MSK2 single and double knockout mouse-derived fibroblasts, phospho-specific immunoblotting, gene expression assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO (single and double knockout), multiple phosphorylation and transcription readouts, replicated independently\",\n      \"pmids\": [\"11909979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MSK1 phosphorylates Bad at Ser112 in vitro and is required for UVB-induced Bad Ser112 phosphorylation in vivo; cells expressing kinase-dead N- or C-terminal MSK1 mutants are defective for UVB-induced Bad phosphorylation; phosphorylation at Ser112 promotes dissociation of Bad from Bcl-XL.\",\n      \"method\": \"In vitro kinase assay, dominant-negative (kinase-dead) MSK1 mutant transfection, immunoblot with phospho-specific antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay + kinase-dead mutants in cells, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"11983683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MSK1 and MSK2 are the major kinases mediating mitogen- and stress-induced phosphorylation of histone H3 and HMG-14 in fibroblasts; MSK1/MSK2 double-knockout mouse embryonic fibroblasts show severely reduced or abolished H3 and HMG-14 phosphorylation; H3 acetylation is unimpaired, and immediate-early genes can still be induced but at reduced efficiency.\",\n      \"method\": \"MSK1/MSK2 double-knockout mice, phospho-specific immunoblotting, immediate-early gene expression assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic double-KO with specific phosphorylation and transcription readouts; resolved prior controversy; widely replicated\",\n      \"pmids\": [\"12773393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MSK1 associates with NF-κB p65 in a stimulus-dependent manner and phosphorylates p65 at Ser276 in the nucleus; this phosphorylation is required for TNF-induced NF-κB transactivation; mutational analysis identifies Ser276 as the MSK1 target on p65.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of p65, reporter gene assays, pharmacological inhibition\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP + in vitro kinase assay + mutagenesis + reporter assays; replicated in multiple subsequent studies\",\n      \"pmids\": [\"12628924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MSK1 is required for full c-fos promoter activation and CREB phosphorylation in response to lysophosphatidic acid (LPA) in mouse ES cells, acting downstream of the ERK pathway.\",\n      \"method\": \"MSK1-knockout ES cells, promoter-reporter assay, phospho-specific immunoblotting\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with functional reporter readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"12769834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MSK1 phosphorylates and activates the transcription factor ER81; MSK1 targets two serine residues on ER81 and enhances ER81-dependent transcription, particularly downstream of p38-MAPK. MSK1 also interacts with co-activators CBP and p300 and stimulates the transactivation domain of CBP.\",\n      \"method\": \"In vitro kinase assay, mutagenesis of ER81 phosphorylation sites, reporter gene assay, Co-IP with CBP/p300\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay + mutagenesis + Co-IP; single lab\",\n      \"pmids\": [\"12569367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of the N-terminal kinase domain of MSK1 (1.8 Å resolution) reveals a unique inactive conformation in which the ATP-binding site is blocked by the nucleotide binding loop, stabilized by a novel three-stranded β-sheet formed by the N terminus, what would be the αB helix, and the activation loop.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure, direct structural determination of the autoinhibitory conformation\",\n      \"pmids\": [\"15274926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MSK1 is required for TGF-β-induced transcriptional responses via the p38α/MSK1 pathway; dominant-interfering MSK1 mutants block Smad3 binding to the co-activator p300 in response to TGF-β, positioning MSK1 as a chromatin-remodeling node integrating Smad and p38 MAPK signaling.\",\n      \"method\": \"Dominant-interfering MSK1 mutants, p38 pharmacological inhibition, Co-IP (Smad3–p300 interaction), transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative mutants + Co-IP + reporter assays; single lab\",\n      \"pmids\": [\"15133024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MSK1 activity is regulated by a multi-site phosphorylation cascade: ERK1/2 or p38 phosphorylate Thr581 and Ser360, activating the C-terminal kinase domain, which autophosphorylates Ser212 (N-terminal T-loop) and Ser376 (hydrophobic motif), both essential for N-terminal kinase domain activity. Ser381 autophosphorylation also supports activity. Activation does not require PDK1, distinguishing MSK1 from RSKs.\",\n      \"method\": \"In vitro kinase assay, alanine-scanning mutagenesis of phosphorylation sites, mass spectrometry, activity assays in cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of ≥6 phosphorylation sites combined with in vitro kinase assays; multiple orthogonal methods in one study\",\n      \"pmids\": [\"15568999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In the suprachiasmatic nucleus (SCN), photic stimulation activates MSK1 via a PACAP-ERK/MAPK-dependent mechanism; MSK1 Ser360 phosphorylation (required for kinase activation) is induced by light during the subjective night; activated ERK and MSK1 co-localize in SCN cell nuclei; MSK1 couples to mPeriod1 clock gene expression via a CREB-dependent mechanism.\",\n      \"method\": \"In vivo phospho-specific immunohistochemistry, MEK inhibitor (U0126) infusion, PACAP receptor antagonist, luciferase reporter assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological epistasis + reporter assay; single lab\",\n      \"pmids\": [\"15930378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MSK1 has a novel phosphorylation site at Thr700 phosphorylated by upstream kinases ERK1/2 and p38α; mutation of Thr700 increases basal MSK1 activity but dramatically reduces Thr581 phosphorylation (essential for activity), consistent with a mechanism whereby Thr700 phosphorylation relieves inhibition by a C-terminal autoinhibitory helix and induces a conformational shift that protects Thr581 from dephosphorylation.\",\n      \"method\": \"Precursor ion scanning mass spectrometry, site-directed mutagenesis, in vitro kinase assays, phospho-specific immunoblotting\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS identification of novel phosphorylation sites + systematic mutagenesis + in vitro kinase assay; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"17117922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MSK1 is the major kinase for Ca2+-ionophore-induced Bad phosphorylation in PC12 cells and cortical neurons; siRNA knockdown of MSK1 reduces Bad phosphorylation; in contrast, knockdown of RSK2 potentiates Bad phosphorylation and elevates ERK phosphorylation, implicating RSK2 in negative-feedback regulation of ERK.\",\n      \"method\": \"siRNA knockdown of MSK1 or RSK2, phospho-specific immunoblotting in PC12 cells and primary cortical neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific siRNA knockdown in two cell types with defined phosphorylation readout; single lab\",\n      \"pmids\": [\"17663748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ca2+-stimulated adenylyl cyclase activity is absolutely required for activation of PKA, MAPK, MSK1, and CREB in hippocampal CA1 pyramidal neurons following contextual fear conditioning; MSK1 is identified as the major CREB kinase activated during training for contextual memory.\",\n      \"method\": \"Fear-conditioning behavioral paradigm, adenylyl cyclase knockout mice, phospho-specific immunohistochemistry\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model (adenylyl cyclase KO) with specific signaling readouts; single lab\",\n      \"pmids\": [\"17196532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MSK1 and MSK2 are required to limit pro-inflammatory cytokine production in macrophages stimulated with LPS by inducing transcription of the MAPK phosphatase DUSP1 and anti-inflammatory cytokine IL-10; MSK1/2 deficiency prevents binding of phosphorylated CREB and ATF1 to the DUSP1 and IL-10 gene promoters; MSK1/2 double-knockout mice are hypersensitive to LPS-induced endotoxic shock.\",\n      \"method\": \"MSK1/MSK2 double-knockout mice and macrophages, cytokine ELISA, chromatin immunoprecipitation (ChIP), endotoxic shock model, contact eczema model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO + ChIP + in vivo disease models; multiple orthogonal methods across multiple biological contexts\",\n      \"pmids\": [\"18690222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Glucocorticoid receptor (GR), upon ligand activation, triggers redistribution of nuclear MSK1 to the cytoplasm via a CRM1-dependent nuclear export mechanism, mediated by a direct protein-protein interaction between liganded GR and activated MSK1; this altered subcellular distribution reduces MSK1 recruitment to inflammatory gene promoters, thereby inhibiting NF-κB p65 transactivation and histone H3 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation (GR–MSK1 interaction), CRM1 inhibitor (leptomycin B), chromatin immunoprecipitation, subcellular fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct protein interaction + CRM1 inhibitor epistasis + ChIP; multiple orthogonal methods in one study\",\n      \"pmids\": [\"18511904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MSK1 phosphorylates RARα at Ser369 in the ligand-binding domain in a p38MAPK-dependent manner; this phosphorylation allows TFIIH binding and subsequent cdk7/cyclin H-mediated phosphorylation of the RARα N-terminal domain at Ser77; MSK1 also phosphorylates histone H3 at Ser10 in this context; the entire p38MAPK/MSK1-initiated cascade controls recruitment of RARα/TFIIH to response elements and target gene activation.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis of RARα phosphorylation sites, chromatin immunoprecipitation, pharmacological inhibition of p38MAPK/MSK1\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + ChIP; multiple orthogonal methods in one study; single lab\",\n      \"pmids\": [\"19078967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MSK1 mediates NF-κB p65 Ser276 phosphorylation induced by p38/ERK MAPK pathways; MSK1 knockdown by siRNA or kinase-dead MSK1 reduces RSV-induced phospho-Ser276 RelA formation; a RelA Ser276Ala mutation abolishes RSV-induced NF-κB-dependent gene expression, establishing that ROS → MSK1 → RelA-Ser276 phosphorylation is a distinct pathway from the pathway controlling RelA cytoplasmic release.\",\n      \"method\": \"siRNA knockdown of MSK1, pharmacological inhibition (H89), expression of RelA Ser276Ala mutant in RelA-/- MEFs, phospho-specific immunoblotting\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — siRNA + pharmacological inhibition + site mutant reconstitution; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"19706715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MSK1 is recruited to inflammatory gene promoters as part of a multi-protein complex containing 14-3-3 phospho-serine adaptor proteins and BRG1 (ATPase subunit of SWI/SNF); MSK1 is recruited by transcription factors such as Elk-1 or NF-κB; following MSK1-mediated H3 Ser10/Ser28 phosphorylation, BRG1 associates with promoters via 14-3-3 scaffolds and SWI/SNF remodels nucleosomes to enable transcription factor binding and transcription onset.\",\n      \"method\": \"Sequential co-immunoprecipitation, sequential chromatin immunoprecipitation (ChIP), MSK1 knockdown cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequential co-IP and sequential ChIP; single lab, two orthogonal methods\",\n      \"pmids\": [\"20129940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MSK1 phosphorylates histone H3 at the c-fos promoter in a CREB-dependent manner; in a reconstituted cell-free system, activators (SRF, Elk-1, CREB, ATF1) bound to their cognate sites recruit MSK1 to phosphorylate H3 Ser10 within chromatin; CREB plays the predominant role, and Ser133 phosphorylation of CREB is essential; the MSK1 N-terminal inhibition domain is critical for chromatin-embedded H3 phosphorylation.\",\n      \"method\": \"Cell-free chromatin reconstitution assay, MSK1 mutagenesis (N-terminal inhibition domain), phospho-specific analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro chromatin system + MSK1 mutagenesis; rigorous mechanistic dissection; single lab\",\n      \"pmids\": [\"20089855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MSK1 is required for induction of the miR-212/132 cluster in primary cortical neurons in response to BDNF; regulation occurs via the ERK1/2 pathway through both MSK-dependent and MSK-independent mechanisms, as shown using MSK1/2 knockout mice and specific inhibitors.\",\n      \"method\": \"MSK1/2 knockout mice, specific kinase inhibitors, deep sequencing, promoter analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO + inhibitor experiments + promoter analysis; single lab\",\n      \"pmids\": [\"20307261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"An acute psychological stressor induces ERK1/2 phosphorylation in dentate gyrus granule neurons within 15 min, leading to nuclear activation of MSK1 and Elk-1; MSK1 and Elk-1 then evoke H3 Ser10 phosphorylation and H3 Lys14 acetylation, resulting in c-Fos and Egr-1 induction; pERK1/2-mediated activation of MSK1 and Elk-1 requires a direct protein-protein interaction between pERK1/2 and activated glucocorticoid receptors.\",\n      \"method\": \"In vivo mouse stress model, co-immunoprecipitation (pERK1/2–GR interaction), phospho-specific immunohistochemistry, ChIP\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo phospho-imaging; single lab\",\n      \"pmids\": [\"21808001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MSK1 is necessary for homeostatic synaptic scaling and experience-dependent synaptic plasticity; neurons from MSK1 kinase-dead knock-in mice fail to show scaling in response to activity deprivation; MSK1 forms part of a BDNF/MAPK-dependent signaling cascade that regulates cell-surface GluA1 expression via induction of Arc/Arg3.1.\",\n      \"method\": \"MSK1 kinase-dead knock-in mice, electrophysiology (synaptic scaling), rescue by WT MSK1 re-expression, GluA1 surface expression assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinase-dead knock-in + rescue experiment + electrophysiology + molecular readout; multiple orthogonal methods\",\n      \"pmids\": [\"22993422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Downregulation of RAS-MAPK-MSK1 pathway components decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice; pharmacological inhibition of pathway components also decreases ATXN1 levels, identifying MSK1 as a node in a genetic network that controls the abundance of the SCA1-causing protein.\",\n      \"method\": \"Parallel cell-based and Drosophila genetic screens, mouse SCA1 model, pharmacological inhibitors, protein level measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screen validated in Drosophila and mouse models with pharmacological confirmation; multiple orthogonal approaches across organisms\",\n      \"pmids\": [\"23719381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MSK1 (Msk1/RPS6KA5) physically interacts with the KMT2A/MLL1 lysine methyltransferase complex by co-immunoprecipitation; the majority of genes regulated by KMT2A/MLL1 knockdown respond comparably to MSK1 knockdown; KMT2A/MLL1 is required for genomic targeting of MSK1 (but not vice versa); MSK1 supports H3K4 methylation by KMT2A/MLL1 by catalyzing H3S10 and H3S28 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation (native and FLAG-tagged), siRNA knockdown, ChIP for H3K4me and H3S10ph at target loci\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP + functional knockdown + ChIP; single lab\",\n      \"pmids\": [\"27895715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MSK1 phosphorylates β-catenin and regulates its nuclear translocation and transcriptional activity in glioblastoma cells; MSK1 is induced after PI3K/mTOR inhibitor treatment; depletion of MSK1 attenuates resistance to PI3K/mTOR inhibitors; MSK1 inhibition plus PI3K/mTOR inhibition synergizes to extend survival in an intracranial animal model.\",\n      \"method\": \"shRNA-mediated MSK1 depletion, phospho-specific immunoblotting of β-catenin Ser552, nuclear fractionation, intracranial mouse model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown + phospho-specific readout + in vivo model; single lab\",\n      \"pmids\": [\"27196759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MSK1 controls expression of luminal differentiation genes GATA3 and FOXA1 by modulating their promoter chromatin status (H3 phosphorylation); MSK1 downregulation impairs breast cancer cell differentiation, increasing bone homing and growth capacities; in vivo genome-wide shRNA screen identified MSK1 as a regulator of metastatic dormancy.\",\n      \"method\": \"In vivo genome-wide shRNA screen, MSK1 knockdown/overexpression, ChIP for histone modifications at GATA3/FOXA1 promoters, in vivo bone metastasis model\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide in vivo screen + ChIP + in vivo metastasis model + chromatin mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"29358704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MSK1 is a downstream target of both early and late ERK activation following DNA damage; early ERK→MSK1 activation (mediated by EGFR) promotes cell survival and DNA repair; late ERK→MSK1 activation (requiring PKCδ) drives apoptosis via a nuclear PKCδ→ERK→MSK1 signaling module; both ERK and MSK1 activations are required for apoptosis in the late phase.\",\n      \"method\": \"shRNA-mediated depletion of MSK1, PKCδ, and EGFR; pharmacological inhibitors (MEK/ERK, EGFR); phospho-specific immunoblotting; in vivo irradiation model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown + pharmacological inhibition + in vivo validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30679314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STAT3 aberrantly transactivates MSK1 gene expression, and MSK1 in turn phosphorylates H3S10 and STAT3 itself; STAT3 forms a functional complex with MSK1 at the NFATc2 promoter to promote its transcription in an H3S10 phosphorylation-dependent manner, creating a positive STAT3-MSK1 feedback loop in gastric carcinogenesis.\",\n      \"method\": \"Co-immunoprecipitation (STAT3–MSK1 complex), ChIP at NFATc2 promoter, MSK1 knockdown/overexpression, xenograft tumor model, phospho-specific immunoblotting\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ChIP + KO/OE with defined readouts; single lab\",\n      \"pmids\": [\"32041943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MSK1 is transcriptionally activated by HOXC6 in pancreatic ductal adenocarcinoma; MSK1 phosphorylates DDX17 to suppress apoptosis; pharmacological inhibition of MSK1 combined with mTOR inhibition potently suppresses PDAC tumor growth and metastasis in mouse models.\",\n      \"method\": \"ChIP (HOXC6 at MSK1 promoter), siRNA/shRNA knockdown, phospho-specific identification of DDX17 as MSK1 substrate, in vivo PDAC mouse models, pharmacological inhibition\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + genetic knockdown + in vivo model; single lab; substrate identification requires further validation\",\n      \"pmids\": [\"37951219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MSK1 regulates BDNF-induced Arc/Arg3.1 expression via phosphorylation of histone H3 at the Arc/Arg3.1 promoter, acting downstream of ERK1/2; however, CREB Ser133 phosphorylation by MSK1 is not required for BDNF-induced Arc/Arg3.1 transcription, as a Ser133Ala CREB knock-in had no effect on induction.\",\n      \"method\": \"MSK1 kinase-dead knock-in mice, ChIP for H3 phosphorylation at Arc promoter, CREB Ser133Ala knock-in mice, pharmacological inhibitors\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead knock-in + CREB knock-in + ChIP; single lab; CREB negative result is directly tested\",\n      \"pmids\": [\"28593137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Glucocorticoid-activated GR physically interacts with activated MSK1 (Co-IP) and drives CRM1-dependent nuclear export of MSK1; this redistribution prevents recruitment of activated MSK1 to inflammatory gene promoters (ChIP), resulting in reduced NF-κB p65 transactivation and histone H3 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, CRM1 inhibitor (leptomycin B), ChIP, subcellular fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + CRM1 pharmacological inhibition + ChIP; multiple orthogonal methods; mechanistically novel\",\n      \"pmids\": [\"18511904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In NIH 3T3 cells, cAMP/forskolin activates p38 in a PKA-dependent fashion; p38 then activates CREB-mediated transcription via MSK1, as shown using dominant-negative MSK1 mutants and H89, but not dominant-negative MSK2 or MAPKAPK2.\",\n      \"method\": \"Dominant-negative mutant transfection, pharmacological inhibitors, reporter gene assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative mutants + pharmacological inhibition + reporter assay; single lab\",\n      \"pmids\": [\"16125054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MSK1 is required for TLR-mediated induction of IL-1ra mRNA and protein from both proximal and distal promoters in macrophages; this occurs via p38 and ERK1/2 MAPK cascades, through both IL-10-dependent and IL-10-independent mechanisms; MSK1/2 knockout mice show decreased IL-1ra production after LPS injection.\",\n      \"method\": \"MSK1/2 knockout macrophages and mice, RT-PCR/ELISA for IL-1ra, promoter-reporter assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vitro and in vivo + promoter analysis; single lab\",\n      \"pmids\": [\"19922413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MSK1 is confined to the nucleus of all expressing cell types in mouse brain (neurons and astroglia), in contrast to RSK1 which localizes to the Golgi apparatus; MSK1 is expressed at highest levels in striatal and olfactory tubercle neurons and in cerebellar Purkinje cells, with lower expression in a subset of astroglia.\",\n      \"method\": \"Immunohistochemistry on adult mouse brain sections\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunolocalization establishing nuclear confinement; replicated across multiple brain regions and cell types; single lab\",\n      \"pmids\": [\"15893597\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSK1 (RPS6KA5) is a nuclear serine/threonine kinase with tandem kinase domains that is directly activated by ERK1/2 or p38 MAPK phosphorylation of Thr581/Thr700 on its C-terminal kinase domain, which then autophosphorylates Ser212 and Ser376 to activate the N-terminal catalytic domain; once active, MSK1 phosphorylates multiple nuclear substrates including CREB (Ser133), ATF1, NF-κB p65 (Ser276), histone H3 (Ser10 and Ser28), HMG-14/HMGN1, RARα, STAT3 (Ser727), Bad (Ser112), and β-catenin, coupling mitogenic and stress signals to chromatin remodeling and transcriptional activation of immediate-early genes, anti-inflammatory mediators (IL-10, DUSP1, IL-1ra), and synaptic plasticity genes; glucocorticoid receptor activation can redistribute MSK1 from nucleus to cytoplasm via CRM1-dependent export, and MSK1 physically associates with the KMT2A/MLL1 methyltransferase complex and the SWI/SNF remodeler through 14-3-3 scaffolds to coordinate chromatin opening at target promoters.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPS6KA5 (MSK1) is a nuclear serine/threonine kinase that couples the ERK1/2 and p38 MAPK cascades to chromatin remodeling and transcription, serving as a terminal effector that converts mitogenic and stress signals into immediate-early gene induction, inflammatory control, and synaptic plasticity [#0, #5, #7]. It is built from two kinase domains in a single polypeptide and is activated by a multi-site phosphorylation cascade: ERK1/2 or p38 phosphorylate the C-terminal kinase domain (Thr581, Ser360, and Thr700), which then autophosphorylates the N-terminal catalytic domain (Ser212, Ser376), with the N-terminal domain held in an autoinhibited conformation by an intramolecular β-sheet seen crystallographically and relieved through this cascade independently of PDK1 [#11, #13, #15]. Once active, MSK1 phosphorylates CREB (Ser133) and ATF1 to drive c-fos and other immediate-early genes [#0, #2, #5], and phosphorylates histone H3 (Ser10, Ser28) and HMGN1/HMG-14 to execute the nucleosomal response [#1, #3, #7]. MSK1 is recruited to target promoters by transcription factors such as Elk-1, CREB, and NF-κB, where its histone phosphorylation creates 14-3-3 docking sites that enable BRG1/SWI/SNF nucleosome remodeling and supports H3K4 methylation by the KMT2A/MLL1 complex with which it associates [#22, #23, #28]. Through phosphorylation of NF-κB p65 (Ser276) and induction of DUSP1, IL-10, and IL-1ra, MSK1 limits pro-inflammatory cytokine output, and MSK1/2-deficient mice are hypersensitive to endotoxic shock [#8, #18, #37]. The kinase additionally phosphorylates STAT3 (Ser727), Bad (Ser112), RARα, ER81, and β-catenin, linking it to apoptosis, nuclear receptor signaling, and oncogenic transcription [#4, #6, #10, #20, #29]. In neurons, MSK1 is the major CREB kinase for contextual fear memory and mediates BDNF-driven Arc/Arg3.1 and miR-212/132 induction underlying synaptic scaling and plasticity [#17, #24, #26]. Glucocorticoid receptor binding to activated MSK1 drives its CRM1-dependent nuclear export, removing it from inflammatory promoters as an anti-inflammatory mechanism [#19, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the founding identity of MSK1 as a dual-kinase-domain nuclear enzyme directly activated by both ERK and p38 and acting as a high-affinity CREB kinase, defining it as a convergence point for mitogenic and stress signaling.\",\n      \"evidence\": \"In vitro kinase assays, inhibitor epistasis (PD98059, SB203580), and localization across multiple cell lines\",\n      \"pmids\": [\"9687510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro substrate preference does not establish the full in vivo substrate set\", \"Activation mechanism of the tandem kinase domains not yet resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Proposed MSK1 as the kinase executing the nucleosomal response by phosphorylating histone H3 Ser10 and HMG-14 downstream of both MAPK arms, linking signaling to chromatin.\",\n      \"evidence\": \"In vitro kinase assay plus H89-based pharmacology in intact cells\",\n      \"pmids\": [\"10469656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"H89 is not fully selective; genetic confirmation was needed\", \"Single lab at this stage\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Provided genetic proof that MSK1 is required for mitogen-induced CREB/ATF1 phosphorylation, separating MSK1-dependent from PKA-dependent CREB activation.\",\n      \"evidence\": \"MSK1 gene-disruption in mouse ES cells with phospho-specific immunoblotting\",\n      \"pmids\": [\"11018520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Possible MSK2 compensation not addressed in single knockout\", \"Downstream transcriptional consequences not quantified here\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Extended the MSK1 substrate repertoire to histone H3 Ser28, STAT3 Ser727, and apoptotic regulation, showing direct phosphorylation in vitro and dependence in cells via kinase-dead mutants.\",\n      \"evidence\": \"In vitro kinase assays, kinase-dead/dominant-negative MSK1 mutants, H89, UV-irradiation cell models\",\n      \"pmids\": [\"11441012\", \"11553624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological stimuli beyond UV irradiation not tested for each substrate\", \"Single-lab findings at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Double-knockout studies established MSK1/MSK2 as the major kinases for stress-induced CREB/ATF1 and identified Bad Ser112 as a substrate, defining MSK1's role in immediate-early gene transcription and apoptotic gating.\",\n      \"evidence\": \"MSK1/MSK2 single and double knockout fibroblasts, in vitro kinase assay, gene expression and phospho readouts\",\n      \"pmids\": [\"11909979\", \"11983683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mitogen-induced transcription was only modestly affected, leaving redundant pathways unexplained\", \"Bad phosphorylation was tested mainly under UVB stress\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined MSK1 as the dominant in vivo H3/HMG-14 kinase and a direct NF-κB p65 Ser276 kinase, embedding it in inflammatory transcription, and broadened its targets to ER81 and the TGF-β/Smad axis.\",\n      \"evidence\": \"MSK1/MSK2 double-knockout mice, reciprocal Co-IP, in vitro kinase assays, mutagenesis, reporter assays\",\n      \"pmids\": [\"12773393\", \"12628924\", \"12569367\", \"12769834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MSK1 is selectively recruited to specific promoters not yet defined\", \"ER81/CBP-p300 and Smad3-p300 links rest on single-lab data\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the activation mechanism, defining the ordered multi-site phosphorylation cascade (Thr581/Ser360 → autophosphorylation of Ser212/Ser376) that is PDK1-independent, distinguishing MSK1 from RSKs.\",\n      \"evidence\": \"Alanine-scanning mutagenesis of ≥6 sites, mass spectrometry, in vitro and cellular kinase assays; with a parallel crystal structure of the autoinhibited N-terminal domain\",\n      \"pmids\": [\"15568999\", \"15274926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length active-state structure not determined\", \"Dynamics of inter-domain communication not directly visualized\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed MSK1 in physiological neuronal and cAMP-driven contexts, showing photic activation in the SCN clock circuit and a PKA→p38→MSK1 route to CREB transcription, and confirmed strict nuclear confinement in brain.\",\n      \"evidence\": \"In vivo phospho-IHC, MEK/PACAP-receptor pharmacology, dominant-negative mutants, reporter assays, brain immunolocalization\",\n      \"pmids\": [\"15930378\", \"16125054\", \"15893597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo epistasis relies on pharmacology rather than genetics\", \"Single-lab observations\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Refined activation by identifying Thr700 as an upstream-phosphorylated regulatory site controlling Thr581 stability, and confirmed MSK1 as the major Ca2+-induced Bad kinase and CREB kinase for contextual memory.\",\n      \"evidence\": \"Precursor-ion-scanning MS, mutagenesis, in vitro kinase assays, siRNA knockdown, adenylyl cyclase knockout mice, fear conditioning\",\n      \"pmids\": [\"17117922\", \"17663748\", \"17196532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proposed C-terminal autoinhibitory helix mechanism inferred indirectly\", \"Behavioral causality of MSK1 not isolated from broader cAMP signaling\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that MSK1/2 enforce anti-inflammatory feedback by inducing DUSP1 and IL-10 via promoter-bound phospho-CREB/ATF1, and uncovered GR-driven CRM1-dependent nuclear export as a mechanism to silence MSK1 at inflammatory promoters.\",\n      \"evidence\": \"MSK1/MSK2 knockout mice and macrophages, ChIP, cytokine ELISA, endotoxic shock model; Co-IP, leptomycin B, subcellular fractionation\",\n      \"pmids\": [\"18690222\", \"18511904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GR-MSK1 interface not mapped\", \"Promoter selectivity of MSK1 recruitment incompletely defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mechanistically connected MSK1 to chromatin remodeling and nuclear receptor licensing: H3 phosphorylation recruits 14-3-3/BRG1-SWI/SNF, and RARα Ser369 phosphorylation enables TFIIH recruitment, while validating p65 Ser276 as a distinct ROS-driven NF-κB pathway.\",\n      \"evidence\": \"Sequential Co-IP and ChIP, in vitro kinase assays, RARα/RelA site mutants, siRNA, knockout mice (IL-1ra)\",\n      \"pmids\": [\"20129940\", \"19078967\", \"19706715\", \"19922413\", \"18511904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Order and stoichiometry of the 14-3-3/SWI-SNF complex assembly not fully resolved\", \"Several findings from single labs\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established a reconstituted mechanism for activator-directed H3 phosphorylation at c-fos and defined MSK1's requirement for synaptic scaling, BDNF-driven Arc and miR-212/132 induction, embedding it in plasticity.\",\n      \"evidence\": \"Cell-free chromatin reconstitution, MSK1 kinase-dead knock-in mice with rescue, electrophysiology, ChIP, deep sequencing\",\n      \"pmids\": [\"20089855\", \"22993422\", \"20307261\", \"28593137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Arc induction was shown to be CREB-Ser133-independent, indicating undefined alternative MSK1 outputs\", \"Causal chain from H3 phosphorylation to GluA1 surface expression not fully traced\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned MSK1 as a disease-relevant transcriptional node controlling protein abundance and tumor behavior, including SCA1-causing ATXN1 levels, breast cancer metastatic dormancy via GATA3/FOXA1, and growth/survival in glioblastoma, gastric, and pancreatic cancers.\",\n      \"evidence\": \"Drosophila and mouse genetic screens, in vivo genome-wide shRNA screen, ChIP, shRNA depletion, phospho-substrate identification, xenograft/intracranial/PDAC models, pharmacological inhibition\",\n      \"pmids\": [\"23719381\", \"29358704\", \"27196759\", \"32041943\", \"37951219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"β-catenin Ser552 and DDX17 as direct MSK1 substrates rest on single studies\", \"Therapeutic combinations validated only in preclinical models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MSK1 achieves promoter and substrate selectivity among its many nuclear targets across distinct physiological contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length active-state structure explaining substrate discrimination\", \"Rules governing context-specific recruitment (transcription factor vs chromatin) not defined\", \"Human disease-causing mutations in RPS6KA5 not established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5, 8, 20, 29]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 3, 7, 23]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 18, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 38]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 5, 7, 30]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 7, 22, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 18, 37]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [17, 24, 26]}\n    ],\n    \"complexes\": [\"KMT2A/MLL1 methyltransferase complex\", \"SWI/SNF (BRG1) remodeling complex\"],\n    \"partners\": [\"CREB\", \"NF-kB p65 (RELA)\", \"STAT3\", \"GR (NR3C1)\", \"14-3-3\", \"BRG1 (SMARCA4)\", \"KMT2A\", \"CBP/p300\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}