{"gene":"RPS6KA1","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":1993,"finding":"ERK2/MAP kinase directly phosphorylates RSK1 in vitro, increasing its 40S ribosomal and peptide kinase activity, retarding its SDS-PAGE migration, and generating new autophosphorylation sites. Activation state correlates with phosphorylation by ERK2, and PP2A dephosphorylation reverses activation.","method":"In vitro kinase assay with purified ERK2, phosphopeptide mapping, PP2A dephosphorylation, epitope-tagged RSK1 expressed in COS cells","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified kinase, multiple orthogonal methods (kinase assay, peptide mapping, PP2A reversal), single lab","pmids":["7688567"],"is_preprint":false},{"year":1995,"finding":"The N-terminal kinase domain of RSK1 mediates substrate phosphorylation, while the C-terminal kinase domain is required for full activation of the N-terminal domain. MAPK phosphorylation site T570 (C-domain) is not required for growth factor-stimulated autophosphorylation or kinase activation. Both domains contribute to autophosphorylation.","method":"Site-directed mutagenesis of kinase-dead and phosphorylation-site mutants of human RSK3 (p90rsk), expressed in COS cells, immune complex kinase assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus multiple substrate and kinase assays in transfected cells, single lab","pmids":["7642538"],"is_preprint":false},{"year":1998,"finding":"Six regulatory phosphorylation sites in MAPKAP-K1a/p90rsk are identified: Ser222 and Ser733 are phosphorylated basally; PMA induces phosphorylation of Thr360, Ser364, Thr574, and Ser381. ERK/MAPK activates the C-terminal kinase domain by phosphorylating Thr574 and contributes to N-terminal domain activation by phosphorylating Ser364. The activated C-terminal domain then autophosphorylates Ser381, which together with Ser364 phosphorylation activates the N-terminal kinase domain.","method":"Phosphopeptide mapping and site-directed mutagenesis in transfected COS-1 cells, in vitro kinase assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of all six sites combined with phosphopeptide mapping and kinase assays, identifying mechanism of sequential domain activation","pmids":["9430688"],"is_preprint":false},{"year":1999,"finding":"RSK1 is phosphorylated by PDK1 within the amino-terminal kinase-activation loop and by ERK in the carboxy-terminal kinase-activation loop. Full activation of RSK1 in vivo requires both PDK1 and ERK; neither alone is sufficient for full-length RSK1 activation.","method":"In vitro kinase assays with purified ERK and PDK1 on isolated RSK1 kinase domains, transfection of HEK 293E cells, PDK1-dependent phosphorylation assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified kinases on isolated domains plus cellular validation, two kinase inputs established","pmids":["10469565"],"is_preprint":false},{"year":1999,"finding":"RSK1 directly phosphorylates the pro-apoptotic protein BAD at Ser112 and Ser136 both in vitro and in vivo, promoting BAD/14-3-3 binding and abrogating BAD's pro-apoptotic function. A constitutively active RSK1 allele promotes cell survival; kinase-dead RSK1 blocks MEK-dependent survival signaling.","method":"In vitro kinase assay, in vivo phosphorylation in IL-3-dependent cells, constitutively active and kinase-dead RSK1 mutants, cell survival assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation plus gain/loss-of-function in cells with defined survival readout, multiple orthogonal methods","pmids":["10679322"],"is_preprint":false},{"year":1999,"finding":"p90RSK phosphorylates BAD at Ser112 in vitro and in vivo in a PKC-dependent pathway, stimulates BAD/14-3-3 binding, and blocks BAD-mediated apoptosis in a Ser112-dependent manner. PKC isoforms tested could not directly phosphorylate BAD, indicating RSK acts as a downstream Bad kinase.","method":"In vitro kinase assay, phorbol ester stimulation in cells, PKC inhibitors, 14-3-3 co-immunoprecipitation, cell death assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphorylation plus cellular co-IP and functional apoptosis assays with pharmacological dissection","pmids":["10574959"],"is_preprint":false},{"year":1999,"finding":"Expression of a constitutively active form of p90Rsk in Xenopus embryos induces cleavage arrest with metaphase spindles characteristic of meiotic metaphase, demonstrating that p90Rsk is a mediator of MAPK-dependent cytostatic factor (CSF) arrest.","method":"Expression of constitutively active Rsk in Xenopus embryos, cytological analysis of arrested blastomeres","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain-of-function in a well-defined biological system (Xenopus embryo) with direct cytological readout","pmids":["10558992"],"is_preprint":false},{"year":2001,"finding":"p90RSK1 and p70 S6 kinase both phosphorylate eEF2 kinase at a conserved serine residue in vitro and inhibit its activity. In response to stimuli that activate ERK (but not mTOR), regulation of eEF2 phosphorylation is blocked by MEK/ERK inhibitors but not rapamycin, consistent with p90RSK1 as the relevant kinase. Regulation of eEF2 requires PDK1.","method":"In vitro phosphorylation of eEF2 kinase by recombinant p90RSK1 and p70S6K; rapamycin and MEK inhibitor pharmacology; PDK1 knockout cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay combined with genetic (PDK1 KO) and pharmacological dissection in multiple cell contexts","pmids":["11500364"],"is_preprint":false},{"year":2001,"finding":"p90Rsk phosphorylates Xenopus Bub1 in vitro and increases its protein kinase activity; injection of constitutively active p90Rsk restores Bub1 activation in MEK-inhibitor-treated oocytes. Bub1 is thus a downstream effector of p90Rsk in meiotic CSF arrest.","method":"In vitro kinase assay with purified p90Rsk and Bub1, constitutively active Rsk injection into oocytes with MEK inhibitor U0126, immune complex kinase assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphorylation plus rescue experiment in oocytes with defined functional readout","pmids":["11231148"],"is_preprint":false},{"year":2001,"finding":"UVA induces phosphorylation of p90RSK at Ser381 via both ERK and JNK pathways. ERK2 and JNK2 (but not p38 kinase) immunoprecipitate with p90RSK after UVA stimulation and phosphorylate p90RSK in vitro. JNK1/2 knockout cells show markedly attenuated p90RSK phosphorylation.","method":"Co-immunoprecipitation, dominant-negative kinase mutants, JNK1/2-null cells, pharmacological inhibitors, in vitro kinase assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus genetic KO plus co-IP in multiple approaches, single lab","pmids":["11278279"],"is_preprint":false},{"year":2001,"finding":"MEK, ERK, and RSK1/2/3 are enriched on mitotic spindle and midbody tubulin in dividing Swiss 3T3 cells. MEK inhibition prevents mitotic exit and alters CDK activities, indicating the MAP kinase pathway coordinates passage through mitosis via RSK.","method":"Subcellular fractionation, immunofluorescence of mitotic cells, MEK inhibitor treatment, CDK activity assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with functional consequence (MEK inhibition blocks mitotic exit), but RSK1 role not fully separated from other RSKs","pmids":["11495723"],"is_preprint":false},{"year":2004,"finding":"Constitutively active RSK1 (but not RSK2) induces neurite outgrowth and differentiation of PC12 cells in the absence of NGF, without activating the endogenous MAPK pathway. PDK1-binding site mutations abolish this activity, indicating RSK1 is sufficient and the only MAPK target required for NGF-induced differentiation.","method":"Transient expression of constitutively active RSK1/RSK2 mutants in PC12 cells, neurite outgrowth assay, PDK1-binding site mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain-of-function with mutagenesis controls in a defined differentiation model, demonstrating RSK1 sufficiency","pmids":["15572664"],"is_preprint":false},{"year":2005,"finding":"p90Rsk is not required for MII cytostatic factor arrest in mouse oocytes. Constitutively active Rsk1 and Rsk2 do not restore MII arrest in mos-/- oocytes, and triple Rsk1/2/3 knockout oocytes show normal CSF arrest. This contrasts with the requirement seen in Xenopus.","method":"Injection of constitutively active Rsk1/Rsk2 into mos-/- oocytes and two-cell embryos; triple RSK knockout mouse oocytes","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic triple knockout plus gain-of-function injection, direct negative result clearly established in mouse vs Xenopus","pmids":["15837801"],"is_preprint":false},{"year":2006,"finding":"Inactive RSK1 interacts with the type I regulatory subunit (RI) of PKA, while active RSK1 interacts with the PKA catalytic subunit (PKAc). These interactions modulate PKA activity (active RSK1 reduces cAMP responsiveness) and determine RSK1 subcellular localization via AKAPs: disrupting AKAP interactions reduces nuclear accumulation of active RSK1, increasing phosphorylation of cytosolic substrates TSC2 and BAD.","method":"Co-immunoprecipitation, subcellular fractionation, dominant-negative AKAP disruption, phosphorylation assays for TSC2 and BAD","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IPs, subcellular redistribution with functional consequence on substrate phosphorylation, multiple orthogonal approaches","pmids":["16738324"],"is_preprint":false},{"year":2006,"finding":"p90Rsk is required for G1-phase arrest in unfertilized starfish eggs downstream of the Mos-MAPK pathway. Inhibition of Rsk with a neutralizing antibody releases G1 arrest and initiates DNA replication; constitutively active Rsk prevents DNA replication after fertilization.","method":"Neutralizing antibody injection, constitutively active Rsk injection into starfish oocytes/eggs, DNA replication assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function in defined cell cycle model with direct DNA replication readout","pmids":["16571626"],"is_preprint":false},{"year":2006,"finding":"IGF-I stimulates p90Rsk activity, which directly phosphorylates Hsp27 in vitro and in vivo. Inhibition of p90Rsk (siRNA or dominant-negative mutant) abolishes IGF-I-induced Hsp27 phosphorylation, and Hsp27 knockdown destabilizes Bad/14-3-3 complexes and increases apoptosis.","method":"In vitro kinase assay, siRNA, dominant-negative p90Rsk, co-immunoprecipitation of Bad/14-3-3","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay for direct phosphorylation plus cellular loss-of-function, single lab","pmids":["20197463"],"is_preprint":false},{"year":2007,"finding":"In Xenopus eggs, Erp1/Emi2 (an APC/C inhibitor) is a direct substrate of p90rsk. Mos-dependent phosphorylation of Erp1 by p90rsk at Thr336, Ser342, and Ser344 stabilizes Erp1 and establishes CSF arrest in meiosis II. Phosphorylation also enhances Erp1 binding to APC/C at its C-terminal destruction box.","method":"In vitro phosphorylation, phosphosite mutagenesis, Xenopus egg extract and oocyte injection experiments, semi-quantitative biochemical analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus functional rescue in Xenopus system, published in Nature","pmids":["17410129"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of the unactivated RSK1 N-terminal kinase domain (NTKD) bound to three different ligands resolved at 2.0 Å. The activation loop and helix αC are disordered in the inactive state; the DFG motif adopts an 'active-like' conformation; and the β-phosphate group in the AMP-PCP complex adopts a unique conformation contributing to inactivity.","method":"X-ray crystallography at 2.0 Å resolution","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with multiple ligand complexes, direct structural evidence for inactive-state features","pmids":["17965187"],"is_preprint":false},{"year":2009,"finding":"RSK1 phosphorylates p27Kip1 at T198, promoting p27 cytoplasmic mislocalization, p27-RhoA binding, RhoA-GTP reduction, loss of actin stress fibers, and increased cell motility. RSK1 co-precipitates with p27 in cells; siRNA to RSK1 rapidly reduces p27pT198; T198-phosphorylated p27 shows increased RhoA binding in vitro.","method":"siRNA knockdown, RSK1 overexpression, in vitro kinase assay, co-immunoprecipitation, RhoA-GTP pull-down, cell motility assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus co-IP plus multiple cellular loss/gain-of-function studies with defined motility readout","pmids":["19470470"],"is_preprint":false},{"year":2009,"finding":"In response to survival signals, Rsk1/2 phosphorylate BimEL on three serine residues in a conserved degron, facilitating binding to βTrCP F-box protein and subsequent proteasomal degradation of BimEL. Erk1/2-mediated phosphorylation of BimEL at Ser69 promotes this Rsk1/2-dependent degron phosphorylation. BimEL phosphorylation mutants unable to bind βTrCP are stabilized and more pro-apoptotic.","method":"Phosphorylation site mutagenesis, co-immunoprecipitation of BimEL with βTrCP, siRNA knockdown of Rsk1/2 and βTrCP, apoptosis assays in NSCLC cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphosite mutagenesis plus co-IP plus functional apoptosis rescue with multiple orthogonal approaches","pmids":["19150432"],"is_preprint":false},{"year":2010,"finding":"RSK1 phosphorylates VASP at T278 (a site regulating actin binding) as identified by co-immunoprecipitation and kinase assay. RSK1 silencing increases lung cancer cell metastatic potential in a zebrafish model.","method":"Kinome-wide siRNA screen, co-immunoprecipitation of RSK1 with VASP and Mena, in vitro phosphorylation of VASP at T278, zebrafish invasion model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP validated interaction plus in vitro phosphorylation of specific site, functional in vivo model, single lab","pmids":["21423205"],"is_preprint":false},{"year":2011,"finding":"Keratin 17 (K17) Ser44 is phosphorylated by RSK1 in skin keratinocytes in response to growth stimuli (serum, EGF, TPA) and cellular stresses. The RSK1 consensus phosphorylation sequence surrounds K17-Ser44, and RSK1 directly phosphorylates this site.","method":"In vitro kinase assay, phospho-specific antibody, mass spectrometry identification, cellular stimulation experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus cellular phosphorylation with MS validation, single lab","pmids":["22006917"],"is_preprint":false},{"year":2011,"finding":"Hypoxia activates p90RSK, which phosphorylates NHE-1, leading to increased Na+/H+ exchange and invadopodia formation in cancer cells. p90RSK inhibition or shRNA depletion blocks hypoxia-induced invadopodia and invasion.","method":"shRNA depletion of NHE-1 and p90RSK, intracellular pH live-cell imaging, invasion assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — shRNA plus pharmacological inhibition with functional readout, but direct in vitro phosphorylation of NHE-1 by p90RSK not shown in abstract","pmids":["22216126"],"is_preprint":false},{"year":2012,"finding":"p90RSK associates with ERK5 and directly phosphorylates ERK5 at S496, inhibiting ERK5 transcriptional activity and upregulating VCAM-1 expression while reducing eNOS. p90RSK and CHIP compete for ERK5 binding at aa571–807; p90RSK activation inhibits ERK5/CHIP association and CHIP ubiquitin ligase activity, increasing ICER levels and promoting cardiac apoptosis.","method":"Co-immunoprecipitation, in vitro phosphorylation of ERK5 S496, ERK5 S496A mutant, dominant-negative p90RSK overexpression, cardiac-specific ERK5 deletion, myocardial infarction mouse model","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation plus mutagenesis plus in vivo gain/loss-of-function with defined cardiac apoptosis readout","pmids":["22267842"],"is_preprint":false},{"year":2012,"finding":"p90RSK also inhibits ERK5 transcriptional activity in endothelial cells by associating with ERK5 and phosphorylating ERK5 S496, upregulating VCAM-1 and reducing eNOS. EC-specific ERK5 knockout increases leukocyte rolling; p90RSK inhibition ameliorates EC dysfunction in diabetic mice via ERK5.","method":"Inducible EC-specific ERK5 knockout mice, p90RSK inhibitor FMK-MEA, VCAM-1 and eNOS expression, co-immunoprecipitation","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic EC-specific knockout plus pharmacological inhibition with in vivo vascular functional readouts, replicated with p90RSK/ERK5 finding from parallel paper","pmids":["23243209"],"is_preprint":false},{"year":2005,"finding":"p90RSK directly phosphorylates cardiac troponin I (cTnI) at Ser23/Ser24 in vitro with high substrate affinity (but not cardiac troponin T). Dominant-negative p90RSK prevents H2O2-mediated cTnI phosphorylation in cardiomyocytes; cardiac-specific p90RSK transgenic mice show increased cTnI Ser23/Ser24 phosphorylation.","method":"In vitro kinase assay, adenovirus-dominant-negative p90RSK, cardiac-specific p90RSK transgenic mice, phospho-specific antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation assay plus transgenic and dominant-negative in vivo models with clear substrate specificity","pmids":["15840586"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of an RSK1 construct in complex with its activator kinase ERK2 is determined; the structure captures a precatalytic state where the RSK1 activation loop faces ERK2's catalytic site. The MAPK-binding linear motif in the disordered RSK1 C-terminal extension binds the ERK2 docking groove to form an encounter complex, and generic kinase domain contacts bring them into a catalytically competent state.","method":"X-ray crystallography, molecular dynamics simulation, biochemical and cellular MAPK→MAPKAPK signaling assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus MD simulation plus biochemical validation, multiple orthogonal methods","pmids":["25730857"],"is_preprint":false},{"year":2015,"finding":"S100B inhibits RSK1 by Ca2+-dependent binding to the CaMK-type (C-terminal) kinase domain of RSK1. Crystallographic, SAXS, and NMR analysis reveal that S100B forms a 'fuzzy' complex with RSK1 peptide ligands; binding involves both conformational selection and induced-fit steps.","method":"X-ray crystallography, SAXS, NMR, fast-kinetics experiments, in vitro biochemical characterization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus SAXS plus NMR plus kinetics, single lab with multiple orthogonal structural methods","pmids":["26527685"],"is_preprint":false},{"year":2015,"finding":"Disturbed flow activates p90RSK, which phosphorylates SENP2 at Thr368, promoting SENP2 nuclear export and reducing SENP2 function. This leads to increased SUMOylation of p53 and ERK5, downregulation of eNOS, upregulation of adhesion molecules and apoptosis, and accelerated atherosclerosis.","method":"In vitro phosphorylation of SENP2 T368, dominant-negative p90RSK mouse model (EC-specific overexpression), SENP2 knockdown, LDLR-KO atherosclerosis model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation plus EC-specific gain/loss-of-function mouse models with defined atherosclerosis readout","pmids":["25689261"],"is_preprint":false},{"year":2006,"finding":"IGF-I/MAPK/p90Rsk signaling promotes nuclear export of Hdm2; constitutively active p90Rsk drives cytoplasmic accumulation of Hdm2 and reduces p53 activity. Constitutively active p90Rsk cooperates with E1A, oncogenic H-Ras, and hTERT to transform normal human fibroblasts (anchorage-independent growth).","method":"Dominant-negative and constitutively active p90Rsk expression, Hdm2/p53 nuclear/cytoplasmic fractionation, anchorage-independent growth assay with multiple oncogenes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function mutants plus transformation assay with defined readout, single lab","pmids":["16621805"],"is_preprint":false},{"year":2010,"finding":"IFNλ activates RSK1 and its downstream effector eIF4B. Prior to IFNλ stimulation, non-active RSK1 is present in a complex with the translational repressor 4E-BP1. IFNλ-induced RSK1 activation causes RSK1 dissociation from 4E-BP1 and allows eIF4F formation and cap-dependent translation; RSK1 is essential for up-regulation of p21WAF1/CIP1.","method":"Co-immunoprecipitation of RSK1 with 4E-BP1 and eIF4B, siRNA knockdown of RSK1, IFNλ stimulation assays, p21 expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP showing complex plus siRNA functional knockdown with translational readout, single lab","pmids":["21075852"],"is_preprint":false},{"year":2009,"finding":"p90RSK phosphorylates NHE1 at Ser703 in adipocytes in response to insulin. RSK1 N-terminal kinase domain inhibitors (BI-D1870, SL0101) block both NHE1 Ser703 phosphorylation and insulin-stimulated glucose uptake, while ERK1/2 inhibition blocks NHE1 phosphorylation but not glucose uptake.","method":"Pharmacological inhibitors selective for RSK N-terminal vs C-terminal domains, phospho-specific antibodies, glucose uptake assays, GLUT4 translocation assays in 3T3-L1 adipocytes","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological dissection with isoform-selective tools, functional glucose transport readout, single lab","pmids":["19765648"],"is_preprint":false},{"year":2010,"finding":"TGFβ activates eEF2 (decreases eEF2 phosphorylation) and inactivates eEF2 kinase via an ERK1/2-dependent increase in p90Rsk phosphorylation. A dominant-negative p90Rsk reverses TGFβ-induced changes in eEF2/eEF2 kinase phosphorylation and significantly attenuates TGFβ-induced protein synthesis and hypertrophy of mesangial cells.","method":"Dominant-negative p90Rsk expression, ERK1/2 inhibition, eEF2 and eEF2 kinase phosphorylation assays, protein synthesis and hypertrophy measurements","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative approach with multiple biochemical readouts, single lab","pmids":["20837011"],"is_preprint":false},{"year":2011,"finding":"RSK1 phosphorylates UBE2R1 (a ubiquitin-conjugating enzyme) at Thr162. Phosphorylation of UBE2R1-T162 promotes its self-ubiquitination and destabilization, reducing UBE2R1-mediated P-glycoprotein (ABCB1) ubiquitination and thereby protecting P-gp from proteasomal degradation. T162D (phosphomimetic) UBE2R1 fails to ubiquitinate P-gp.","method":"In vitro kinase assay of RSK1 on UBE2R1, phosphomimetic/alanine mutants, ubiquitination assays, P-gp expression and drug sensitivity assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus functional substrate ubiquitination assay, single lab","pmids":["27786305"],"is_preprint":false},{"year":2008,"finding":"ERK-RSK1 (but not RSK2) activation by growth factors at G2 phase delays G2/M transition in HeLa cells, delays cyclin B1-associated kinase activation and nuclear translocation of cyclin B1, and reduces chromosomal segregation defects. siRNA knockdown specifically of RSK1 (not RSK2) abrogates the G2/M delay.","method":"siRNA knockdown of RSK1 vs RSK2, FACS, mitotic index, time-lapse microscopy, cyclin B1 kinase and localization assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific siRNA knockdown with multiple cell cycle readouts, single lab","pmids":["18450423"],"is_preprint":false},{"year":1998,"finding":"Metabotropic glutamate receptor stimulation in hippocampal slices induces a rapid PKC-dependent translocation of p90rsk to polyribosomes, with concomitant enhanced phosphorylation of at least six polyribosome-binding proteins. Both ERK-2 (the p90rsk-activating kinase) and glycogen synthase kinase 3β (a known p90rsk substrate) are present on polyribosomes.","method":"Subcellular fractionation of hippocampal slices, immunoblotting, PKC inhibition, metabotropic glutamate receptor stimulation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — subcellular fractionation with functional correlation, single lab, direct phosphorylation not reconstituted in vitro","pmids":["9844018"],"is_preprint":false},{"year":2021,"finding":"In pancreatic cancer, RSK1 selectively interacts with membrane-bound mutant KRASG12D (identified by proximity labeling/BioID mass spectrometry). This interaction requires NF1 and SPRED2. Membrane RSK1 mediates negative feedback on wild-type RAS signaling and impedes pancreatic cancer cell proliferation upon ablation of mutant KRAS.","method":"BioID proximity labeling, mass spectrometry, co-immunoprecipitation, RSK1 ablation studies in murine PDAC cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proximity labeling MS plus functional ablation, interaction validated by co-IP, single lab","pmids":["34021083"],"is_preprint":false},{"year":2019,"finding":"FLT3-ITD activates RSK1/2 through MEK/ERK and PDK1 pathways. RSK1 phosphorylates S6RP at S235/S236, TSC2 at S1798, eIF4B at S422 (and cooperatively at S406 with PIM), thereby activating mTORC1/S6K/4EBP1 and eIF4B to promote cap-dependent translation. RSK1 also phosphorylates Bad at S75 and downregulates BIM-EL cooperatively with ERK.","method":"Phospho-specific antibodies, RSK inhibitors (BI-D1870), siRNA knockdown, FLT3-ITD cell lines, proliferation/apoptosis assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological and genetic loss-of-function on multiple substrates, single lab, no in vitro kinase reconstitution described in abstract","pmids":["31756944"],"is_preprint":false},{"year":2022,"finding":"IL11-stimulated ERK/P90RSK activity causes phosphorylation of LKB1 at S325 and S428, leading to LKB1 inactivation, AMPK inhibition, and mTOR activation across stromal, epithelial, and hepatocyte cell types. This drives myofibroblast transformation, SNAI1 expression, and epithelial dysfunction.","method":"Phospho-specific antibodies for LKB1, AMPK, mTOR; pharmacological ERK inhibition; genetic manipulation of IL11 signaling in mice","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic in vivo validation with multiple cell types and substrates, single lab, no in vitro kinase assay described","pmids":["35992082"],"is_preprint":false},{"year":2022,"finding":"RSK1 is required for axon regeneration in dorsal root ganglion neurons after sciatic nerve injury. Mechanistically, RSK1 preferentially regulates the synthesis of regeneration-related proteins (identified by ribosomal profiling). RSK1 expression is upregulated in injured DRG but not retinal ganglion cells; RSK1 overexpression enhances PTEN-deletion-induced axon regeneration in the CNS.","method":"Chemical inhibitor screening, gain- and loss-of-function analyses, ribosomal profiling, sciatic nerve injury model, retinal ganglion cell CNS model","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional approaches including ribosomal profiling, gain/loss-of-function in two neuronal models, single lab","pmids":["35648763"],"is_preprint":false},{"year":2010,"finding":"The YopM effector of Yersinia binds RSK1 through its C-terminal domain (from LRR12 to C-terminus); this interaction domain is distinct from the LRR6–LRR15 region required for PRK2 binding. Both RSK1 and PRK2 interaction domains of YopM are required for IL-10 induction in vivo and for virulence, establishing RSK1 as a host kinase exploited by a bacterial pathogen.","method":"In vitro binding assays with YopM truncation mutants, co-immunoprecipitation, murine infection models","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — systematic domain mapping with in vitro binding plus in vivo infection model, direct mechanistic link between RSK1 binding and IL-10 induction","pmids":["20515922"],"is_preprint":false}],"current_model":"RPS6KA1 (RSK1/p90RSK) is a dual-kinase domain AGC serine/threonine kinase activated sequentially by ERK-mediated phosphorylation of the C-terminal kinase domain activation loop (T574/Ser364) followed by autophosphorylation of Ser381 and PDK1-mediated phosphorylation of the N-terminal kinase domain activation loop (Ser222), with the N-terminal domain executing substrate phosphorylation; RSK1 promotes cell survival by directly phosphorylating and inactivating pro-apoptotic proteins BAD and BimEL, regulates translation elongation by phosphorylating and inhibiting eEF2 kinase, controls cell motility via p27T198-RhoA interactions and VASP phosphorylation, mediates meiotic CSF arrest in Xenopus (but not mouse) oocytes through Erp1/Emi2 and Bub1 phosphorylation, regulates endothelial function and atherosclerosis by phosphorylating ERK5-S496 and SENP2-T368, and modulates protein synthesis, cytoskeletal organization, and mitotic progression through multiple substrates including NHE1, cTnI, LKB1, and UBE2R1."},"narrative":{"mechanistic_narrative":"RPS6KA1 (RSK1/p90RSK) is a dual-kinase-domain serine/threonine kinase that converts ERK/MAPK pathway signals into phosphorylation of diverse cytoplasmic and nuclear substrates controlling cell survival, motility, translation, and cell-cycle progression [PMID:7688567, PMID:10679322]. Its activation is sequential and bipartite: ERK phosphorylates the C-terminal kinase domain (CTKD) activation loop and the linker, the activated CTKD autophosphorylates Ser381, and PDK1 phosphorylates the N-terminal kinase domain (NTKD) activation loop, so that full activity requires both ERK and PDK1 inputs while the NTKD executes substrate phosphorylation [PMID:9430688, PMID:10469565, PMID:7642538]. Structural work resolved the inactive NTKD and captured a precatalytic RSK1–ERK2 encounter complex in which a docking motif in the disordered RSK1 C-terminal extension engages the ERK2 docking groove, while Ca2+-loaded S100B binds the CTKD to inhibit the kinase [PMID:17965187, PMID:25730857, PMID:26527685]. RSK1 promotes survival by directly phosphorylating BAD at Ser112/Ser136 to drive 14-3-3 sequestration and by phosphorylating a BimEL degron to trigger βTrCP-dependent degradation [PMID:10679322, PMID:19150432]. It regulates protein synthesis through inhibitory phosphorylation of eEF2 kinase and engagement of the eIF4B/4E-BP1 translational machinery [PMID:11500364, PMID:21075852], and controls cell motility and invasion by phosphorylating p27Kip1 at Thr198, VASP, and NHE1 [PMID:19470470, PMID:21423205, PMID:19765648]. In the cardiovascular system RSK1 phosphorylates ERK5 at Ser496 and SENP2 at Thr368 to drive endothelial dysfunction and atherosclerosis, and phosphorylates cardiac troponin I at Ser23/24 [PMID:22267842, PMID:25689261, PMID:15840586]. RSK1 also mediates MAPK-dependent meiotic CSF arrest in Xenopus oocytes via Erp1/Emi2 and Bub1 phosphorylation, a role that is dispensable in mouse oocytes [PMID:17410129, PMID:11231148, PMID:15837801].","teleology":[{"year":1993,"claim":"Established that RSK1 is a direct downstream effector of the MAP kinase cascade, defining the upstream activating input.","evidence":"In vitro kinase assay with purified ERK2, phosphopeptide mapping, and PP2A reversal on tagged RSK1 from COS cells","pmids":["7688567"],"confidence":"High","gaps":["Did not resolve which phosphosites drive activation","Did not distinguish roles of the two kinase domains"]},{"year":1995,"claim":"Resolved the division of labor between RSK's two kinase domains, showing the NTKD phosphorylates substrates while the CTKD enables NTKD activation.","evidence":"Site-directed mutagenesis of kinase-dead and phosphosite mutants expressed in COS cells with immune-complex kinase assays","pmids":["7642538"],"confidence":"High","gaps":["Full set of regulatory phosphosites not yet mapped","Role of an additional upstream kinase beyond MAPK unclear"]},{"year":1998,"claim":"Mapped the six regulatory phosphosites and defined the sequential intramolecular activation mechanism downstream of ERK.","evidence":"Systematic phosphopeptide mapping and mutagenesis of all six sites in COS-1 cells with in vitro kinase assays","pmids":["9430688"],"confidence":"High","gaps":["Identity of the NTKD activation-loop kinase not yet established","Mechanism of CTKD-to-NTKD signal transfer structurally undefined"]},{"year":1999,"claim":"Identified PDK1 as the second obligatory upstream kinase, establishing dual ERK + PDK1 control of full RSK1 activation.","evidence":"In vitro kinase assays with purified ERK and PDK1 on isolated RSK1 domains plus HEK293E cellular validation","pmids":["10469565"],"confidence":"High","gaps":["Spatial/temporal coordination of the two inputs in cells unresolved"]},{"year":1999,"claim":"Defined RSK1's pro-survival output by demonstrating direct BAD phosphorylation that triggers 14-3-3 sequestration and blocks apoptosis.","evidence":"In vitro and in vivo phosphorylation, 14-3-3 co-IP, constitutively active and kinase-dead RSK1 mutants with survival assays","pmids":["10679322","10574959"],"confidence":"High","gaps":["Relative in vivo contribution of RSK1 versus other BAD kinases not delineated"]},{"year":1999,"claim":"Placed RSK1 as a mediator of MAPK-dependent cytostatic factor arrest, opening the meiotic/cell-cycle axis.","evidence":"Expression of constitutively active Rsk in Xenopus embryos with cytological analysis of arrested blastomeres","pmids":["10558992"],"confidence":"High","gaps":["Direct CSF substrates not yet identified","Species generality untested at this stage"]},{"year":2001,"claim":"Connected RSK1 to translational control via inhibitory phosphorylation of eEF2 kinase distinct from the mTOR/p70S6K route.","evidence":"In vitro phosphorylation by recombinant RSK1, rapamycin/MEK inhibitor pharmacology, and PDK1-null cells","pmids":["11500364"],"confidence":"High","gaps":["Phosphosite on eEF2 kinase not pinpointed in this work","Quantitative contribution to elongation control unresolved"]},{"year":2001,"claim":"Identified Bub1 as a CSF-relevant RSK1 substrate, extending the meiotic arrest mechanism.","evidence":"In vitro kinase assay on purified Bub1 plus constitutively active Rsk rescue in MEK-inhibited oocytes","pmids":["11231148"],"confidence":"High","gaps":["Bub1 phosphosites and structural basis not defined"]},{"year":2001,"claim":"Showed RSK1 can receive stress-pathway input (JNK) in addition to ERK and localizes to mitotic structures, broadening its activation logic and cell-cycle reach.","evidence":"Co-IP, dominant-negative mutants, JNK1/2-null cells, and immunofluorescence/fractionation of mitotic cells","pmids":["11278279","11495723"],"confidence":"High","gaps":["RSK1-specific mitotic role not separated from RSK2/RSK3 [#10]","Functional consequence of JNK-driven phosphorylation incompletely defined"]},{"year":2006,"claim":"Established subcellular targeting control of RSK1 through PKA subunit and AKAP interactions that dictate access to cytosolic versus nuclear substrates.","evidence":"Reciprocal co-IPs, subcellular fractionation, AKAP disruption, and TSC2/BAD phosphorylation readouts","pmids":["16738324"],"confidence":"High","gaps":["Identity of relevant AKAPs in vivo not resolved","Generality across cell types untested"]},{"year":2007,"claim":"Resolved the direct CSF substrate Erp1/Emi2 and the phosphosites stabilizing APC/C inhibition, mechanistically completing the Xenopus meiotic arrest pathway.","evidence":"In vitro phosphorylation, phosphosite mutagenesis, and Xenopus egg-extract/oocyte injection rescue","pmids":["17410129"],"confidence":"High","gaps":["Did not address whether the same axis operates in mammals"]},{"year":2005,"claim":"Distinguished RSK1 species-specificity in CSF arrest by showing it is dispensable in mouse oocytes, refining the meiotic model.","evidence":"Constitutively active Rsk injection into mos-/- oocytes and triple Rsk1/2/3 knockout mouse oocytes","pmids":["15837801"],"confidence":"High","gaps":["Identity of the mouse CSF effector replacing RSK function unresolved"]},{"year":2009,"claim":"Defined RSK1's pro-motility output via p27Kip1-T198 phosphorylation that mislocalizes p27, sequesters RhoA, and disassembles stress fibers.","evidence":"In vitro kinase assay, co-IP, RhoA-GTP pull-down, siRNA/overexpression, and motility assays","pmids":["19470470"],"confidence":"High","gaps":["In vivo invasion relevance not addressed in this study"]},{"year":2009,"claim":"Extended pro-survival signaling by showing RSK1/2 phosphorylate a BimEL degron to drive βTrCP-mediated proteasomal degradation.","evidence":"Phosphosite mutagenesis, BimEL/βTrCP co-IP, Rsk/βTrCP siRNA, and apoptosis assays in NSCLC cells","pmids":["19150432"],"confidence":"High","gaps":["RSK1 versus RSK2 individual contributions not separated"]},{"year":2012,"claim":"Established RSK1 as a driver of endothelial/cardiac dysfunction by phosphorylating ERK5-S496 to suppress its transcriptional activity.","evidence":"In vitro phosphorylation, S496A mutant, dominant-negative RSK1, EC-specific ERK5 knockout, and myocardial infarction/diabetic mouse models","pmids":["22267842","23243209"],"confidence":"High","gaps":["Direct in vivo demonstration that RSK1 is the unique S496 kinase in disease incompletely isolated"]},{"year":2015,"claim":"Identified SENP2-T368 phosphorylation as a RSK1 mechanism linking disturbed flow to SUMO-dependent endothelial dysfunction and atherosclerosis.","evidence":"In vitro phosphorylation, EC-specific dominant-negative RSK1 mice, SENP2 knockdown, and LDLR-KO atherosclerosis model","pmids":["25689261"],"confidence":"High","gaps":["Interplay with the ERK5-S496 arm not fully integrated"]},{"year":2015,"claim":"Provided structural insight into how ERK2 engages and how S100B inhibits RSK1, defining activation and regulatory interfaces.","evidence":"X-ray crystallography of the RSK1–ERK2 precatalytic complex with MD; crystallography/SAXS/NMR/kinetics of S100B–RSK1","pmids":["25730857","26527685"],"confidence":"High","gaps":["Full-length two-domain activated structure not captured","Cellular consequences of S100B inhibition not quantified"]},{"year":2011,"claim":"Expanded the substrate repertoire into cytoskeletal, ion-transport, and ubiquitin-machinery control via NHE1, K17-Ser44, and UBE2R1-T162.","evidence":"In vitro kinase assays, phosphomimetic mutants, ubiquitination and pH/invadopodia assays","pmids":["27786305","22006917","22216126"],"confidence":"Medium","gaps":["Some links (e.g. NHE1 in hypoxia) lack direct in vitro phosphorylation [#22]","Physiological weighting of these substrates unclear"]},{"year":2021,"claim":"Revealed a membrane-proximal RSK1 pool that engages mutant KRAS in a NF1/SPRED2-dependent manner to enforce negative feedback on RAS signaling.","evidence":"BioID proximity labeling, mass spectrometry, co-IP, and RSK1 ablation in murine PDAC cells","pmids":["34021083"],"confidence":"Medium","gaps":["Direct biochemical contact versus proximity not fully resolved","Generality beyond pancreatic context untested"]},{"year":2022,"claim":"Implicated RSK1 in translation-dependent axon regeneration and in IL11-driven LKB1/AMPK/mTOR dysregulation, broadening its physiological roles.","evidence":"Ribosomal profiling and gain/loss-of-function in nerve injury models; phospho-LKB1 readouts with ERK inhibition in mice","pmids":["35648763","35992082"],"confidence":"Medium","gaps":["LKB1 phosphorylation by RSK1 not reconstituted in vitro [#38]","RSK1-specific regeneration substrates only partially defined"]},{"year":null,"claim":"How RSK1 substrate selection is governed across its many reported targets in different tissues, and whether distinct activation inputs (ERK vs JNK) or localization pools dictate specific outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking subcellular targeting to substrate choice","Isoform-specific (RSK1 vs RSK2/3) substrate boundaries incompletely mapped","In vivo hierarchy of survival vs motility vs translational outputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,7,16,18,19,23,25,28,33]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[17,26]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[36]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,26]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,19]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[16,12,34]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,30,37]}],"complexes":[],"partners":["ERK2","PDK1","S100B","BAD","ERK5","P27KIP1","4E-BP1","KRAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15418","full_name":"Ribosomal protein S6 kinase alpha-1","aliases":["90 kDa ribosomal protein S6 kinase 1","p90-RSK 1","p90RSK1","p90S6K","MAP kinase-activated protein kinase 1a","MAPK-activated protein kinase 1a","MAPKAP kinase 1a","MAPKAPK-1a","Ribosomal S6 kinase 1","RSK-1"],"length_aa":735,"mass_kda":82.7,"function":"Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1 (PubMed:10679322, PubMed:12213813, PubMed:15117958, PubMed:16223362, PubMed:17360704, PubMed:18722121, PubMed:26158630, PubMed:35772404, PubMed:9430688). In fibroblast, is required for EGF-stimulated phosphorylation of CREB1, which results in the subsequent transcriptional activation of several immediate-early genes (PubMed:18508509, PubMed:18813292). In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP (PubMed:12213813, PubMed:16223362). Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity (PubMed:18508509, PubMed:18813292). Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the pre-initiation complex (PubMed:17360704). In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation (PubMed:16763566). Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway (PubMed:15342917). Also involved in feedback regulation of mTORC1 and mTORC2 by phosphorylating DEPTOR (PubMed:22017876). Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function (PubMed:10679322, PubMed:16213824). Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4) (PubMed:11684016). Mediates induction of hepatocyte prolifration by TGFA through phosphorylation of CEBPB (PubMed:18508509, PubMed:18813292). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression (PubMed:18508509, PubMed:18813292). Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). In response to mTORC1 activation, phosphorylates EIF4B at 'Ser-406' and 'Ser-422' which stimulates bicarbonate cotransporter SLC4A7 mRNA translation, increasing SLC4A7 protein abundance and function (PubMed:35772404) (Microbial infection) Promotes the late transcription and translation of viral lytic genes during Kaposi's sarcoma-associated herpesvirus/HHV-8 infection, when constitutively activated","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15418/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RPS6KA1","classification":"Not Classified","n_dependent_lines":43,"n_total_lines":1208,"dependency_fraction":0.03559602649006623},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000117676","cell_line_id":"CID001261","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"CDC37","stoichiometry":0.2},{"gene":"RPS6KA3","stoichiometry":0.2},{"gene":"RPS6KA4","stoichiometry":0.2},{"gene":"TRRAP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001261","total_profiled":1310},"omim":[{"mim_id":"617517","title":"RIBOSOMAL PROTEIN S6 KINASE C1; RPS6KC1","url":"https://www.omim.org/entry/617517"},{"mim_id":"603607","title":"RIBOSOMAL PROTEIN S6 KINASE A5; RPS6KA5","url":"https://www.omim.org/entry/603607"},{"mim_id":"602006","title":"MITOGEN-ACTIVATED PROTEIN KINASE-ACTIVATED PROTEIN KINASE 2; MAPKAPK2","url":"https://www.omim.org/entry/602006"},{"mim_id":"601685","title":"RIBOSOMAL PROTEIN S6 KINASE A2; RPS6KA2","url":"https://www.omim.org/entry/601685"},{"mim_id":"601684","title":"RIBOSOMAL PROTEIN S6 KINASE A1; RPS6KA1","url":"https://www.omim.org/entry/601684"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPS6KA1"},"hgnc":{"alias_symbol":["RSK1","HU-1","p90Rsk","MAPKAPK1"],"prev_symbol":[]},"alphafold":{"accession":"Q15418","domains":[{"cath_id":"3.30.200.20","chopping":"50-145_347-384","consensus_level":"medium","plddt":78.6295,"start":50,"end":384},{"cath_id":"1.10.510.10","chopping":"146-341","consensus_level":"medium","plddt":87.5619,"start":146,"end":341},{"cath_id":"3.30.200.20","chopping":"413-489","consensus_level":"high","plddt":88.4922,"start":413,"end":489},{"cath_id":"1.10.510.10","chopping":"496-707","consensus_level":"high","plddt":81.8986,"start":496,"end":707}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15418","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15418-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15418-F1-predicted_aligned_error_v6.png","plddt_mean":76.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPS6KA1","jax_strain_url":"https://www.jax.org/strain/search?query=RPS6KA1"},"sequence":{"accession":"Q15418","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15418.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15418/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15418"}},"corpus_meta":[{"pmid":"11500364","id":"PMC_11500364","title":"Regulation 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Activation state correlates with phosphorylation by ERK2, and PP2A dephosphorylation reverses activation.\",\n      \"method\": \"In vitro kinase assay with purified ERK2, phosphopeptide mapping, PP2A dephosphorylation, epitope-tagged RSK1 expressed in COS cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified kinase, multiple orthogonal methods (kinase assay, peptide mapping, PP2A reversal), single lab\",\n      \"pmids\": [\"7688567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The N-terminal kinase domain of RSK1 mediates substrate phosphorylation, while the C-terminal kinase domain is required for full activation of the N-terminal domain. MAPK phosphorylation site T570 (C-domain) is not required for growth factor-stimulated autophosphorylation or kinase activation. Both domains contribute to autophosphorylation.\",\n      \"method\": \"Site-directed mutagenesis of kinase-dead and phosphorylation-site mutants of human RSK3 (p90rsk), expressed in COS cells, immune complex kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus multiple substrate and kinase assays in transfected cells, single lab\",\n      \"pmids\": [\"7642538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Six regulatory phosphorylation sites in MAPKAP-K1a/p90rsk are identified: Ser222 and Ser733 are phosphorylated basally; PMA induces phosphorylation of Thr360, Ser364, Thr574, and Ser381. ERK/MAPK activates the C-terminal kinase domain by phosphorylating Thr574 and contributes to N-terminal domain activation by phosphorylating Ser364. The activated C-terminal domain then autophosphorylates Ser381, which together with Ser364 phosphorylation activates the N-terminal kinase domain.\",\n      \"method\": \"Phosphopeptide mapping and site-directed mutagenesis in transfected COS-1 cells, in vitro kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of all six sites combined with phosphopeptide mapping and kinase assays, identifying mechanism of sequential domain activation\",\n      \"pmids\": [\"9430688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RSK1 is phosphorylated by PDK1 within the amino-terminal kinase-activation loop and by ERK in the carboxy-terminal kinase-activation loop. Full activation of RSK1 in vivo requires both PDK1 and ERK; neither alone is sufficient for full-length RSK1 activation.\",\n      \"method\": \"In vitro kinase assays with purified ERK and PDK1 on isolated RSK1 kinase domains, transfection of HEK 293E cells, PDK1-dependent phosphorylation assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified kinases on isolated domains plus cellular validation, two kinase inputs established\",\n      \"pmids\": [\"10469565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RSK1 directly phosphorylates the pro-apoptotic protein BAD at Ser112 and Ser136 both in vitro and in vivo, promoting BAD/14-3-3 binding and abrogating BAD's pro-apoptotic function. A constitutively active RSK1 allele promotes cell survival; kinase-dead RSK1 blocks MEK-dependent survival signaling.\",\n      \"method\": \"In vitro kinase assay, in vivo phosphorylation in IL-3-dependent cells, constitutively active and kinase-dead RSK1 mutants, cell survival assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation plus gain/loss-of-function in cells with defined survival readout, multiple orthogonal methods\",\n      \"pmids\": [\"10679322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"p90RSK phosphorylates BAD at Ser112 in vitro and in vivo in a PKC-dependent pathway, stimulates BAD/14-3-3 binding, and blocks BAD-mediated apoptosis in a Ser112-dependent manner. PKC isoforms tested could not directly phosphorylate BAD, indicating RSK acts as a downstream Bad kinase.\",\n      \"method\": \"In vitro kinase assay, phorbol ester stimulation in cells, PKC inhibitors, 14-3-3 co-immunoprecipitation, cell death assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro phosphorylation plus cellular co-IP and functional apoptosis assays with pharmacological dissection\",\n      \"pmids\": [\"10574959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Expression of a constitutively active form of p90Rsk in Xenopus embryos induces cleavage arrest with metaphase spindles characteristic of meiotic metaphase, demonstrating that p90Rsk is a mediator of MAPK-dependent cytostatic factor (CSF) arrest.\",\n      \"method\": \"Expression of constitutively active Rsk in Xenopus embryos, cytological analysis of arrested blastomeres\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in a well-defined biological system (Xenopus embryo) with direct cytological readout\",\n      \"pmids\": [\"10558992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"p90RSK1 and p70 S6 kinase both phosphorylate eEF2 kinase at a conserved serine residue in vitro and inhibit its activity. In response to stimuli that activate ERK (but not mTOR), regulation of eEF2 phosphorylation is blocked by MEK/ERK inhibitors but not rapamycin, consistent with p90RSK1 as the relevant kinase. Regulation of eEF2 requires PDK1.\",\n      \"method\": \"In vitro phosphorylation of eEF2 kinase by recombinant p90RSK1 and p70S6K; rapamycin and MEK inhibitor pharmacology; PDK1 knockout cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay combined with genetic (PDK1 KO) and pharmacological dissection in multiple cell contexts\",\n      \"pmids\": [\"11500364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"p90Rsk phosphorylates Xenopus Bub1 in vitro and increases its protein kinase activity; injection of constitutively active p90Rsk restores Bub1 activation in MEK-inhibitor-treated oocytes. Bub1 is thus a downstream effector of p90Rsk in meiotic CSF arrest.\",\n      \"method\": \"In vitro kinase assay with purified p90Rsk and Bub1, constitutively active Rsk injection into oocytes with MEK inhibitor U0126, immune complex kinase assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro phosphorylation plus rescue experiment in oocytes with defined functional readout\",\n      \"pmids\": [\"11231148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"UVA induces phosphorylation of p90RSK at Ser381 via both ERK and JNK pathways. ERK2 and JNK2 (but not p38 kinase) immunoprecipitate with p90RSK after UVA stimulation and phosphorylate p90RSK in vitro. JNK1/2 knockout cells show markedly attenuated p90RSK phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative kinase mutants, JNK1/2-null cells, pharmacological inhibitors, in vitro kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus genetic KO plus co-IP in multiple approaches, single lab\",\n      \"pmids\": [\"11278279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MEK, ERK, and RSK1/2/3 are enriched on mitotic spindle and midbody tubulin in dividing Swiss 3T3 cells. MEK inhibition prevents mitotic exit and alters CDK activities, indicating the MAP kinase pathway coordinates passage through mitosis via RSK.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence of mitotic cells, MEK inhibitor treatment, CDK activity assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with functional consequence (MEK inhibition blocks mitotic exit), but RSK1 role not fully separated from other RSKs\",\n      \"pmids\": [\"11495723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Constitutively active RSK1 (but not RSK2) induces neurite outgrowth and differentiation of PC12 cells in the absence of NGF, without activating the endogenous MAPK pathway. PDK1-binding site mutations abolish this activity, indicating RSK1 is sufficient and the only MAPK target required for NGF-induced differentiation.\",\n      \"method\": \"Transient expression of constitutively active RSK1/RSK2 mutants in PC12 cells, neurite outgrowth assay, PDK1-binding site mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with mutagenesis controls in a defined differentiation model, demonstrating RSK1 sufficiency\",\n      \"pmids\": [\"15572664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p90Rsk is not required for MII cytostatic factor arrest in mouse oocytes. Constitutively active Rsk1 and Rsk2 do not restore MII arrest in mos-/- oocytes, and triple Rsk1/2/3 knockout oocytes show normal CSF arrest. This contrasts with the requirement seen in Xenopus.\",\n      \"method\": \"Injection of constitutively active Rsk1/Rsk2 into mos-/- oocytes and two-cell embryos; triple RSK knockout mouse oocytes\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic triple knockout plus gain-of-function injection, direct negative result clearly established in mouse vs Xenopus\",\n      \"pmids\": [\"15837801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Inactive RSK1 interacts with the type I regulatory subunit (RI) of PKA, while active RSK1 interacts with the PKA catalytic subunit (PKAc). These interactions modulate PKA activity (active RSK1 reduces cAMP responsiveness) and determine RSK1 subcellular localization via AKAPs: disrupting AKAP interactions reduces nuclear accumulation of active RSK1, increasing phosphorylation of cytosolic substrates TSC2 and BAD.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, dominant-negative AKAP disruption, phosphorylation assays for TSC2 and BAD\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IPs, subcellular redistribution with functional consequence on substrate phosphorylation, multiple orthogonal approaches\",\n      \"pmids\": [\"16738324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"p90Rsk is required for G1-phase arrest in unfertilized starfish eggs downstream of the Mos-MAPK pathway. Inhibition of Rsk with a neutralizing antibody releases G1 arrest and initiates DNA replication; constitutively active Rsk prevents DNA replication after fertilization.\",\n      \"method\": \"Neutralizing antibody injection, constitutively active Rsk injection into starfish oocytes/eggs, DNA replication assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function in defined cell cycle model with direct DNA replication readout\",\n      \"pmids\": [\"16571626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IGF-I stimulates p90Rsk activity, which directly phosphorylates Hsp27 in vitro and in vivo. Inhibition of p90Rsk (siRNA or dominant-negative mutant) abolishes IGF-I-induced Hsp27 phosphorylation, and Hsp27 knockdown destabilizes Bad/14-3-3 complexes and increases apoptosis.\",\n      \"method\": \"In vitro kinase assay, siRNA, dominant-negative p90Rsk, co-immunoprecipitation of Bad/14-3-3\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay for direct phosphorylation plus cellular loss-of-function, single lab\",\n      \"pmids\": [\"20197463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Xenopus eggs, Erp1/Emi2 (an APC/C inhibitor) is a direct substrate of p90rsk. Mos-dependent phosphorylation of Erp1 by p90rsk at Thr336, Ser342, and Ser344 stabilizes Erp1 and establishes CSF arrest in meiosis II. Phosphorylation also enhances Erp1 binding to APC/C at its C-terminal destruction box.\",\n      \"method\": \"In vitro phosphorylation, phosphosite mutagenesis, Xenopus egg extract and oocyte injection experiments, semi-quantitative biochemical analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus functional rescue in Xenopus system, published in Nature\",\n      \"pmids\": [\"17410129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of the unactivated RSK1 N-terminal kinase domain (NTKD) bound to three different ligands resolved at 2.0 Å. The activation loop and helix αC are disordered in the inactive state; the DFG motif adopts an 'active-like' conformation; and the β-phosphate group in the AMP-PCP complex adopts a unique conformation contributing to inactivity.\",\n      \"method\": \"X-ray crystallography at 2.0 Å resolution\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with multiple ligand complexes, direct structural evidence for inactive-state features\",\n      \"pmids\": [\"17965187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RSK1 phosphorylates p27Kip1 at T198, promoting p27 cytoplasmic mislocalization, p27-RhoA binding, RhoA-GTP reduction, loss of actin stress fibers, and increased cell motility. RSK1 co-precipitates with p27 in cells; siRNA to RSK1 rapidly reduces p27pT198; T198-phosphorylated p27 shows increased RhoA binding in vitro.\",\n      \"method\": \"siRNA knockdown, RSK1 overexpression, in vitro kinase assay, co-immunoprecipitation, RhoA-GTP pull-down, cell motility assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus co-IP plus multiple cellular loss/gain-of-function studies with defined motility readout\",\n      \"pmids\": [\"19470470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In response to survival signals, Rsk1/2 phosphorylate BimEL on three serine residues in a conserved degron, facilitating binding to βTrCP F-box protein and subsequent proteasomal degradation of BimEL. Erk1/2-mediated phosphorylation of BimEL at Ser69 promotes this Rsk1/2-dependent degron phosphorylation. BimEL phosphorylation mutants unable to bind βTrCP are stabilized and more pro-apoptotic.\",\n      \"method\": \"Phosphorylation site mutagenesis, co-immunoprecipitation of BimEL with βTrCP, siRNA knockdown of Rsk1/2 and βTrCP, apoptosis assays in NSCLC cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphosite mutagenesis plus co-IP plus functional apoptosis rescue with multiple orthogonal approaches\",\n      \"pmids\": [\"19150432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RSK1 phosphorylates VASP at T278 (a site regulating actin binding) as identified by co-immunoprecipitation and kinase assay. RSK1 silencing increases lung cancer cell metastatic potential in a zebrafish model.\",\n      \"method\": \"Kinome-wide siRNA screen, co-immunoprecipitation of RSK1 with VASP and Mena, in vitro phosphorylation of VASP at T278, zebrafish invasion model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP validated interaction plus in vitro phosphorylation of specific site, functional in vivo model, single lab\",\n      \"pmids\": [\"21423205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Keratin 17 (K17) Ser44 is phosphorylated by RSK1 in skin keratinocytes in response to growth stimuli (serum, EGF, TPA) and cellular stresses. The RSK1 consensus phosphorylation sequence surrounds K17-Ser44, and RSK1 directly phosphorylates this site.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, mass spectrometry identification, cellular stimulation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus cellular phosphorylation with MS validation, single lab\",\n      \"pmids\": [\"22006917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hypoxia activates p90RSK, which phosphorylates NHE-1, leading to increased Na+/H+ exchange and invadopodia formation in cancer cells. p90RSK inhibition or shRNA depletion blocks hypoxia-induced invadopodia and invasion.\",\n      \"method\": \"shRNA depletion of NHE-1 and p90RSK, intracellular pH live-cell imaging, invasion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — shRNA plus pharmacological inhibition with functional readout, but direct in vitro phosphorylation of NHE-1 by p90RSK not shown in abstract\",\n      \"pmids\": [\"22216126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p90RSK associates with ERK5 and directly phosphorylates ERK5 at S496, inhibiting ERK5 transcriptional activity and upregulating VCAM-1 expression while reducing eNOS. p90RSK and CHIP compete for ERK5 binding at aa571–807; p90RSK activation inhibits ERK5/CHIP association and CHIP ubiquitin ligase activity, increasing ICER levels and promoting cardiac apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphorylation of ERK5 S496, ERK5 S496A mutant, dominant-negative p90RSK overexpression, cardiac-specific ERK5 deletion, myocardial infarction mouse model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation plus mutagenesis plus in vivo gain/loss-of-function with defined cardiac apoptosis readout\",\n      \"pmids\": [\"22267842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p90RSK also inhibits ERK5 transcriptional activity in endothelial cells by associating with ERK5 and phosphorylating ERK5 S496, upregulating VCAM-1 and reducing eNOS. EC-specific ERK5 knockout increases leukocyte rolling; p90RSK inhibition ameliorates EC dysfunction in diabetic mice via ERK5.\",\n      \"method\": \"Inducible EC-specific ERK5 knockout mice, p90RSK inhibitor FMK-MEA, VCAM-1 and eNOS expression, co-immunoprecipitation\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic EC-specific knockout plus pharmacological inhibition with in vivo vascular functional readouts, replicated with p90RSK/ERK5 finding from parallel paper\",\n      \"pmids\": [\"23243209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p90RSK directly phosphorylates cardiac troponin I (cTnI) at Ser23/Ser24 in vitro with high substrate affinity (but not cardiac troponin T). Dominant-negative p90RSK prevents H2O2-mediated cTnI phosphorylation in cardiomyocytes; cardiac-specific p90RSK transgenic mice show increased cTnI Ser23/Ser24 phosphorylation.\",\n      \"method\": \"In vitro kinase assay, adenovirus-dominant-negative p90RSK, cardiac-specific p90RSK transgenic mice, phospho-specific antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation assay plus transgenic and dominant-negative in vivo models with clear substrate specificity\",\n      \"pmids\": [\"15840586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of an RSK1 construct in complex with its activator kinase ERK2 is determined; the structure captures a precatalytic state where the RSK1 activation loop faces ERK2's catalytic site. The MAPK-binding linear motif in the disordered RSK1 C-terminal extension binds the ERK2 docking groove to form an encounter complex, and generic kinase domain contacts bring them into a catalytically competent state.\",\n      \"method\": \"X-ray crystallography, molecular dynamics simulation, biochemical and cellular MAPK→MAPKAPK signaling assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus MD simulation plus biochemical validation, multiple orthogonal methods\",\n      \"pmids\": [\"25730857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"S100B inhibits RSK1 by Ca2+-dependent binding to the CaMK-type (C-terminal) kinase domain of RSK1. Crystallographic, SAXS, and NMR analysis reveal that S100B forms a 'fuzzy' complex with RSK1 peptide ligands; binding involves both conformational selection and induced-fit steps.\",\n      \"method\": \"X-ray crystallography, SAXS, NMR, fast-kinetics experiments, in vitro biochemical characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus SAXS plus NMR plus kinetics, single lab with multiple orthogonal structural methods\",\n      \"pmids\": [\"26527685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Disturbed flow activates p90RSK, which phosphorylates SENP2 at Thr368, promoting SENP2 nuclear export and reducing SENP2 function. This leads to increased SUMOylation of p53 and ERK5, downregulation of eNOS, upregulation of adhesion molecules and apoptosis, and accelerated atherosclerosis.\",\n      \"method\": \"In vitro phosphorylation of SENP2 T368, dominant-negative p90RSK mouse model (EC-specific overexpression), SENP2 knockdown, LDLR-KO atherosclerosis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation plus EC-specific gain/loss-of-function mouse models with defined atherosclerosis readout\",\n      \"pmids\": [\"25689261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IGF-I/MAPK/p90Rsk signaling promotes nuclear export of Hdm2; constitutively active p90Rsk drives cytoplasmic accumulation of Hdm2 and reduces p53 activity. Constitutively active p90Rsk cooperates with E1A, oncogenic H-Ras, and hTERT to transform normal human fibroblasts (anchorage-independent growth).\",\n      \"method\": \"Dominant-negative and constitutively active p90Rsk expression, Hdm2/p53 nuclear/cytoplasmic fractionation, anchorage-independent growth assay with multiple oncogenes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function mutants plus transformation assay with defined readout, single lab\",\n      \"pmids\": [\"16621805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IFNλ activates RSK1 and its downstream effector eIF4B. Prior to IFNλ stimulation, non-active RSK1 is present in a complex with the translational repressor 4E-BP1. IFNλ-induced RSK1 activation causes RSK1 dissociation from 4E-BP1 and allows eIF4F formation and cap-dependent translation; RSK1 is essential for up-regulation of p21WAF1/CIP1.\",\n      \"method\": \"Co-immunoprecipitation of RSK1 with 4E-BP1 and eIF4B, siRNA knockdown of RSK1, IFNλ stimulation assays, p21 expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP showing complex plus siRNA functional knockdown with translational readout, single lab\",\n      \"pmids\": [\"21075852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p90RSK phosphorylates NHE1 at Ser703 in adipocytes in response to insulin. RSK1 N-terminal kinase domain inhibitors (BI-D1870, SL0101) block both NHE1 Ser703 phosphorylation and insulin-stimulated glucose uptake, while ERK1/2 inhibition blocks NHE1 phosphorylation but not glucose uptake.\",\n      \"method\": \"Pharmacological inhibitors selective for RSK N-terminal vs C-terminal domains, phospho-specific antibodies, glucose uptake assays, GLUT4 translocation assays in 3T3-L1 adipocytes\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological dissection with isoform-selective tools, functional glucose transport readout, single lab\",\n      \"pmids\": [\"19765648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TGFβ activates eEF2 (decreases eEF2 phosphorylation) and inactivates eEF2 kinase via an ERK1/2-dependent increase in p90Rsk phosphorylation. A dominant-negative p90Rsk reverses TGFβ-induced changes in eEF2/eEF2 kinase phosphorylation and significantly attenuates TGFβ-induced protein synthesis and hypertrophy of mesangial cells.\",\n      \"method\": \"Dominant-negative p90Rsk expression, ERK1/2 inhibition, eEF2 and eEF2 kinase phosphorylation assays, protein synthesis and hypertrophy measurements\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative approach with multiple biochemical readouts, single lab\",\n      \"pmids\": [\"20837011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RSK1 phosphorylates UBE2R1 (a ubiquitin-conjugating enzyme) at Thr162. Phosphorylation of UBE2R1-T162 promotes its self-ubiquitination and destabilization, reducing UBE2R1-mediated P-glycoprotein (ABCB1) ubiquitination and thereby protecting P-gp from proteasomal degradation. T162D (phosphomimetic) UBE2R1 fails to ubiquitinate P-gp.\",\n      \"method\": \"In vitro kinase assay of RSK1 on UBE2R1, phosphomimetic/alanine mutants, ubiquitination assays, P-gp expression and drug sensitivity assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus functional substrate ubiquitination assay, single lab\",\n      \"pmids\": [\"27786305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERK-RSK1 (but not RSK2) activation by growth factors at G2 phase delays G2/M transition in HeLa cells, delays cyclin B1-associated kinase activation and nuclear translocation of cyclin B1, and reduces chromosomal segregation defects. siRNA knockdown specifically of RSK1 (not RSK2) abrogates the G2/M delay.\",\n      \"method\": \"siRNA knockdown of RSK1 vs RSK2, FACS, mitotic index, time-lapse microscopy, cyclin B1 kinase and localization assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific siRNA knockdown with multiple cell cycle readouts, single lab\",\n      \"pmids\": [\"18450423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Metabotropic glutamate receptor stimulation in hippocampal slices induces a rapid PKC-dependent translocation of p90rsk to polyribosomes, with concomitant enhanced phosphorylation of at least six polyribosome-binding proteins. Both ERK-2 (the p90rsk-activating kinase) and glycogen synthase kinase 3β (a known p90rsk substrate) are present on polyribosomes.\",\n      \"method\": \"Subcellular fractionation of hippocampal slices, immunoblotting, PKC inhibition, metabotropic glutamate receptor stimulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — subcellular fractionation with functional correlation, single lab, direct phosphorylation not reconstituted in vitro\",\n      \"pmids\": [\"9844018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In pancreatic cancer, RSK1 selectively interacts with membrane-bound mutant KRASG12D (identified by proximity labeling/BioID mass spectrometry). This interaction requires NF1 and SPRED2. Membrane RSK1 mediates negative feedback on wild-type RAS signaling and impedes pancreatic cancer cell proliferation upon ablation of mutant KRAS.\",\n      \"method\": \"BioID proximity labeling, mass spectrometry, co-immunoprecipitation, RSK1 ablation studies in murine PDAC cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proximity labeling MS plus functional ablation, interaction validated by co-IP, single lab\",\n      \"pmids\": [\"34021083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FLT3-ITD activates RSK1/2 through MEK/ERK and PDK1 pathways. RSK1 phosphorylates S6RP at S235/S236, TSC2 at S1798, eIF4B at S422 (and cooperatively at S406 with PIM), thereby activating mTORC1/S6K/4EBP1 and eIF4B to promote cap-dependent translation. RSK1 also phosphorylates Bad at S75 and downregulates BIM-EL cooperatively with ERK.\",\n      \"method\": \"Phospho-specific antibodies, RSK inhibitors (BI-D1870), siRNA knockdown, FLT3-ITD cell lines, proliferation/apoptosis assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological and genetic loss-of-function on multiple substrates, single lab, no in vitro kinase reconstitution described in abstract\",\n      \"pmids\": [\"31756944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL11-stimulated ERK/P90RSK activity causes phosphorylation of LKB1 at S325 and S428, leading to LKB1 inactivation, AMPK inhibition, and mTOR activation across stromal, epithelial, and hepatocyte cell types. This drives myofibroblast transformation, SNAI1 expression, and epithelial dysfunction.\",\n      \"method\": \"Phospho-specific antibodies for LKB1, AMPK, mTOR; pharmacological ERK inhibition; genetic manipulation of IL11 signaling in mice\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic in vivo validation with multiple cell types and substrates, single lab, no in vitro kinase assay described\",\n      \"pmids\": [\"35992082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RSK1 is required for axon regeneration in dorsal root ganglion neurons after sciatic nerve injury. Mechanistically, RSK1 preferentially regulates the synthesis of regeneration-related proteins (identified by ribosomal profiling). RSK1 expression is upregulated in injured DRG but not retinal ganglion cells; RSK1 overexpression enhances PTEN-deletion-induced axon regeneration in the CNS.\",\n      \"method\": \"Chemical inhibitor screening, gain- and loss-of-function analyses, ribosomal profiling, sciatic nerve injury model, retinal ganglion cell CNS model\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional approaches including ribosomal profiling, gain/loss-of-function in two neuronal models, single lab\",\n      \"pmids\": [\"35648763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The YopM effector of Yersinia binds RSK1 through its C-terminal domain (from LRR12 to C-terminus); this interaction domain is distinct from the LRR6–LRR15 region required for PRK2 binding. Both RSK1 and PRK2 interaction domains of YopM are required for IL-10 induction in vivo and for virulence, establishing RSK1 as a host kinase exploited by a bacterial pathogen.\",\n      \"method\": \"In vitro binding assays with YopM truncation mutants, co-immunoprecipitation, murine infection models\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — systematic domain mapping with in vitro binding plus in vivo infection model, direct mechanistic link between RSK1 binding and IL-10 induction\",\n      \"pmids\": [\"20515922\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPS6KA1 (RSK1/p90RSK) is a dual-kinase domain AGC serine/threonine kinase activated sequentially by ERK-mediated phosphorylation of the C-terminal kinase domain activation loop (T574/Ser364) followed by autophosphorylation of Ser381 and PDK1-mediated phosphorylation of the N-terminal kinase domain activation loop (Ser222), with the N-terminal domain executing substrate phosphorylation; RSK1 promotes cell survival by directly phosphorylating and inactivating pro-apoptotic proteins BAD and BimEL, regulates translation elongation by phosphorylating and inhibiting eEF2 kinase, controls cell motility via p27T198-RhoA interactions and VASP phosphorylation, mediates meiotic CSF arrest in Xenopus (but not mouse) oocytes through Erp1/Emi2 and Bub1 phosphorylation, regulates endothelial function and atherosclerosis by phosphorylating ERK5-S496 and SENP2-T368, and modulates protein synthesis, cytoskeletal organization, and mitotic progression through multiple substrates including NHE1, cTnI, LKB1, and UBE2R1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPS6KA1 (RSK1/p90RSK) is a dual-kinase-domain serine/threonine kinase that converts ERK/MAPK pathway signals into phosphorylation of diverse cytoplasmic and nuclear substrates controlling cell survival, motility, translation, and cell-cycle progression [#0, #4]. Its activation is sequential and bipartite: ERK phosphorylates the C-terminal kinase domain (CTKD) activation loop and the linker, the activated CTKD autophosphorylates Ser381, and PDK1 phosphorylates the N-terminal kinase domain (NTKD) activation loop, so that full activity requires both ERK and PDK1 inputs while the NTKD executes substrate phosphorylation [#2, #3, #1]. Structural work resolved the inactive NTKD and captured a precatalytic RSK1\\u2013ERK2 encounter complex in which a docking motif in the disordered RSK1 C-terminal extension engages the ERK2 docking groove, while Ca2+-loaded S100B binds the CTKD to inhibit the kinase [#17, #26, #27]. RSK1 promotes survival by directly phosphorylating BAD at Ser112/Ser136 to drive 14-3-3 sequestration and by phosphorylating a BimEL degron to trigger \\u03b2TrCP-dependent degradation [#4, #19]. It regulates protein synthesis through inhibitory phosphorylation of eEF2 kinase and engagement of the eIF4B/4E-BP1 translational machinery [#7, #30], and controls cell motility and invasion by phosphorylating p27Kip1 at Thr198, VASP, and NHE1 [#18, #20, #31]. In the cardiovascular system RSK1 phosphorylates ERK5 at Ser496 and SENP2 at Thr368 to drive endothelial dysfunction and atherosclerosis, and phosphorylates cardiac troponin I at Ser23/24 [#23, #28, #25]. RSK1 also mediates MAPK-dependent meiotic CSF arrest in Xenopus oocytes via Erp1/Emi2 and Bub1 phosphorylation, a role that is dispensable in mouse oocytes [#16, #8, #12].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that RSK1 is a direct downstream effector of the MAP kinase cascade, defining the upstream activating input.\",\n      \"evidence\": \"In vitro kinase assay with purified ERK2, phosphopeptide mapping, and PP2A reversal on tagged RSK1 from COS cells\",\n      \"pmids\": [\"7688567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which phosphosites drive activation\", \"Did not distinguish roles of the two kinase domains\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved the division of labor between RSK's two kinase domains, showing the NTKD phosphorylates substrates while the CTKD enables NTKD activation.\",\n      \"evidence\": \"Site-directed mutagenesis of kinase-dead and phosphosite mutants expressed in COS cells with immune-complex kinase assays\",\n      \"pmids\": [\"7642538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of regulatory phosphosites not yet mapped\", \"Role of an additional upstream kinase beyond MAPK unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapped the six regulatory phosphosites and defined the sequential intramolecular activation mechanism downstream of ERK.\",\n      \"evidence\": \"Systematic phosphopeptide mapping and mutagenesis of all six sites in COS-1 cells with in vitro kinase assays\",\n      \"pmids\": [\"9430688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the NTKD activation-loop kinase not yet established\", \"Mechanism of CTKD-to-NTKD signal transfer structurally undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified PDK1 as the second obligatory upstream kinase, establishing dual ERK + PDK1 control of full RSK1 activation.\",\n      \"evidence\": \"In vitro kinase assays with purified ERK and PDK1 on isolated RSK1 domains plus HEK293E cellular validation\",\n      \"pmids\": [\"10469565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial/temporal coordination of the two inputs in cells unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined RSK1's pro-survival output by demonstrating direct BAD phosphorylation that triggers 14-3-3 sequestration and blocks apoptosis.\",\n      \"evidence\": \"In vitro and in vivo phosphorylation, 14-3-3 co-IP, constitutively active and kinase-dead RSK1 mutants with survival assays\",\n      \"pmids\": [\"10679322\", \"10574959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of RSK1 versus other BAD kinases not delineated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed RSK1 as a mediator of MAPK-dependent cytostatic factor arrest, opening the meiotic/cell-cycle axis.\",\n      \"evidence\": \"Expression of constitutively active Rsk in Xenopus embryos with cytological analysis of arrested blastomeres\",\n      \"pmids\": [\"10558992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CSF substrates not yet identified\", \"Species generality untested at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected RSK1 to translational control via inhibitory phosphorylation of eEF2 kinase distinct from the mTOR/p70S6K route.\",\n      \"evidence\": \"In vitro phosphorylation by recombinant RSK1, rapamycin/MEK inhibitor pharmacology, and PDK1-null cells\",\n      \"pmids\": [\"11500364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite on eEF2 kinase not pinpointed in this work\", \"Quantitative contribution to elongation control unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified Bub1 as a CSF-relevant RSK1 substrate, extending the meiotic arrest mechanism.\",\n      \"evidence\": \"In vitro kinase assay on purified Bub1 plus constitutively active Rsk rescue in MEK-inhibited oocytes\",\n      \"pmids\": [\"11231148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bub1 phosphosites and structural basis not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed RSK1 can receive stress-pathway input (JNK) in addition to ERK and localizes to mitotic structures, broadening its activation logic and cell-cycle reach.\",\n      \"evidence\": \"Co-IP, dominant-negative mutants, JNK1/2-null cells, and immunofluorescence/fractionation of mitotic cells\",\n      \"pmids\": [\"11278279\", \"11495723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RSK1-specific mitotic role not separated from RSK2/RSK3 [#10]\", \"Functional consequence of JNK-driven phosphorylation incompletely defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established subcellular targeting control of RSK1 through PKA subunit and AKAP interactions that dictate access to cytosolic versus nuclear substrates.\",\n      \"evidence\": \"Reciprocal co-IPs, subcellular fractionation, AKAP disruption, and TSC2/BAD phosphorylation readouts\",\n      \"pmids\": [\"16738324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of relevant AKAPs in vivo not resolved\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the direct CSF substrate Erp1/Emi2 and the phosphosites stabilizing APC/C inhibition, mechanistically completing the Xenopus meiotic arrest pathway.\",\n      \"evidence\": \"In vitro phosphorylation, phosphosite mutagenesis, and Xenopus egg-extract/oocyte injection rescue\",\n      \"pmids\": [\"17410129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether the same axis operates in mammals\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished RSK1 species-specificity in CSF arrest by showing it is dispensable in mouse oocytes, refining the meiotic model.\",\n      \"evidence\": \"Constitutively active Rsk injection into mos-/- oocytes and triple Rsk1/2/3 knockout mouse oocytes\",\n      \"pmids\": [\"15837801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the mouse CSF effector replacing RSK function unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined RSK1's pro-motility output via p27Kip1-T198 phosphorylation that mislocalizes p27, sequesters RhoA, and disassembles stress fibers.\",\n      \"evidence\": \"In vitro kinase assay, co-IP, RhoA-GTP pull-down, siRNA/overexpression, and motility assays\",\n      \"pmids\": [\"19470470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo invasion relevance not addressed in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended pro-survival signaling by showing RSK1/2 phosphorylate a BimEL degron to drive \\u03b2TrCP-mediated proteasomal degradation.\",\n      \"evidence\": \"Phosphosite mutagenesis, BimEL/\\u03b2TrCP co-IP, Rsk/\\u03b2TrCP siRNA, and apoptosis assays in NSCLC cells\",\n      \"pmids\": [\"19150432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RSK1 versus RSK2 individual contributions not separated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established RSK1 as a driver of endothelial/cardiac dysfunction by phosphorylating ERK5-S496 to suppress its transcriptional activity.\",\n      \"evidence\": \"In vitro phosphorylation, S496A mutant, dominant-negative RSK1, EC-specific ERK5 knockout, and myocardial infarction/diabetic mouse models\",\n      \"pmids\": [\"22267842\", \"23243209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vivo demonstration that RSK1 is the unique S496 kinase in disease incompletely isolated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified SENP2-T368 phosphorylation as a RSK1 mechanism linking disturbed flow to SUMO-dependent endothelial dysfunction and atherosclerosis.\",\n      \"evidence\": \"In vitro phosphorylation, EC-specific dominant-negative RSK1 mice, SENP2 knockdown, and LDLR-KO atherosclerosis model\",\n      \"pmids\": [\"25689261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay with the ERK5-S496 arm not fully integrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided structural insight into how ERK2 engages and how S100B inhibits RSK1, defining activation and regulatory interfaces.\",\n      \"evidence\": \"X-ray crystallography of the RSK1\\u2013ERK2 precatalytic complex with MD; crystallography/SAXS/NMR/kinetics of S100B\\u2013RSK1\",\n      \"pmids\": [\"25730857\", \"26527685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length two-domain activated structure not captured\", \"Cellular consequences of S100B inhibition not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expanded the substrate repertoire into cytoskeletal, ion-transport, and ubiquitin-machinery control via NHE1, K17-Ser44, and UBE2R1-T162.\",\n      \"evidence\": \"In vitro kinase assays, phosphomimetic mutants, ubiquitination and pH/invadopodia assays\",\n      \"pmids\": [\"27786305\", \"22006917\", \"22216126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Some links (e.g. NHE1 in hypoxia) lack direct in vitro phosphorylation [#22]\", \"Physiological weighting of these substrates unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a membrane-proximal RSK1 pool that engages mutant KRAS in a NF1/SPRED2-dependent manner to enforce negative feedback on RAS signaling.\",\n      \"evidence\": \"BioID proximity labeling, mass spectrometry, co-IP, and RSK1 ablation in murine PDAC cells\",\n      \"pmids\": [\"34021083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical contact versus proximity not fully resolved\", \"Generality beyond pancreatic context untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated RSK1 in translation-dependent axon regeneration and in IL11-driven LKB1/AMPK/mTOR dysregulation, broadening its physiological roles.\",\n      \"evidence\": \"Ribosomal profiling and gain/loss-of-function in nerve injury models; phospho-LKB1 readouts with ERK inhibition in mice\",\n      \"pmids\": [\"35648763\", \"35992082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LKB1 phosphorylation by RSK1 not reconstituted in vitro [#38]\", \"RSK1-specific regeneration substrates only partially defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RSK1 substrate selection is governed across its many reported targets in different tissues, and whether distinct activation inputs (ERK vs JNK) or localization pools dictate specific outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking subcellular targeting to substrate choice\", \"Isoform-specific (RSK1 vs RSK2/3) substrate boundaries incompletely mapped\", \"In vivo hierarchy of survival vs motility vs translational outputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 7, 16, 18, 19, 23, 25, 28, 33]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [17, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 19]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [16, 12, 34]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 30, 37]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ERK2\", \"PDK1\", \"S100B\", \"BAD\", \"ERK5\", \"p27Kip1\", \"4E-BP1\", \"KRAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}