{"gene":"MAPK7","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1995,"finding":"BMK1/ERK5 is a new mammalian MAP kinase of 816 amino acids with a TEY dual phosphorylation motif (like ERK1/2) but with a distinct C-terminal domain and loop-12 structure, suggesting unique signaling functions.","method":"Molecular cloning, sequence analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary cloning paper with sequence characterization and structural analysis, single lab","pmids":["7646528"],"is_preprint":false},{"year":1996,"finding":"BMK1/ERK5 is a redox-sensitive kinase selectively activated by H2O2 (but not by angiotensin II, phorbol ester, PDGF, or TNF-α) in a calcium-dependent manner in vascular smooth muscle cells, demonstrating activation distinct from ERK1/2.","method":"Kinase activity assays, pharmacological inhibition, calcium chelation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase activation assays with multiple stimuli and inhibitors, single lab","pmids":["8663194"],"is_preprint":false},{"year":1998,"finding":"ERK5/BMK1 physically interacts with MEF2 transcription factors (interaction mapped to the MADS/MEF2 domain of MEF2); ERK5 phosphorylates MEF2 in vitro and enhances MEF2 transactivation capacity when co-expressed.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, in vitro kinase assay, reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (Y2H, GST pulldown, Co-IP, in vitro kinase assay, reporter assay) in single study","pmids":["9753748"],"is_preprint":false},{"year":1998,"finding":"EGF-mediated activation of BMK1/ERK5 occurs independently of Ras and requires MEK5; expression of dominant-negative BMK1 blocks EGF-induced cell proliferation and prevents S-phase entry, establishing BMK1 as required for EGF-induced cell proliferation.","method":"Dominant-negative expression, cell cycle analysis, BrdU incorporation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dominant-negative approach with defined cell-cycle phenotype, published in Nature with multiple complementary experiments","pmids":["9790194"],"is_preprint":false},{"year":1999,"finding":"ERK5 is activated by EGF and NGF downstream of receptor tyrosine kinases via a Ras-dependent pathway; ERK5 phosphorylates the Ets-domain transcription factor Sap1a (but not Elk1) in vitro and in cells, and the ERK5 pathway mediates serum-induced c-Fos expression and serum response element transcription via Sap1a.","method":"Dominant-negative expression, reporter assay, in vitro kinase assay, phosphatase inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus reporter assays plus dominant-negative genetics in multiple cell contexts","pmids":["10473620"],"is_preprint":false},{"year":1999,"finding":"MEKK3 physically interacts with MEK5 (identified by yeast two-hybrid, confirmed by co-immunoprecipitation) and, as a dominant-active form, stimulates BMK1 activity through MEK5; endogenous MEKK3 activity is required for growth factor-mediated BMK1 activation.","method":"Yeast two-hybrid, co-immunoprecipitation, dominant-active/dominant-negative expression, kinase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — Y2H plus reciprocal Co-IP plus functional kinase cascade reconstitution in cells","pmids":["10593883"],"is_preprint":false},{"year":1999,"finding":"Fluid shear stress potently activates BMK1/ERK5 in endothelial cells via a mechanism dependent on non-Src tyrosine kinases and intracellular calcium, but not on Src, redox state, NO, PKA, PKC, PKG, CaM kinase, PI3K, or arachidonic acid metabolism.","method":"Kinase activity assay, pharmacological inhibitors, overexpression of kinase-inactive c-Src, calcium chelation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase assay with multiple mechanistic dissection experiments, single lab","pmids":["9867822"],"is_preprint":false},{"year":2000,"finding":"MEKK2 binds MEK5 (identified by yeast two-hybrid), activates BMK1/ERK5 through MEK5, and this activation is cell-type specific (MEKK3 required in Cos7/HEK293; MEKK2 required in D10 T cells); MEKK2 also interacts with the T cell adapter Lad/RIBP and co-localizes at the T cell-APC contact site.","method":"Yeast two-hybrid, co-immunoprecipitation, dominant-negative expression, kinase assay, co-localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — Y2H plus Co-IP plus functional kinase assays plus co-localization across multiple cell types","pmids":["11073940"],"is_preprint":false},{"year":2000,"finding":"ERK5 contains a C-terminal transcriptional activation domain (TAD) and a MEF2-interacting domain in its C-terminal half; these domains are required for coactivation of MEF2D, and the MEF2-ERK5 interaction is activation-dependent in vivo and inhibitable by the MEF2 repressor Cabin1.","method":"Yeast two-hybrid, reporter assay, domain deletion/mutagenesis, promoter activation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional domain mapping with mutagenesis plus reporter assays plus Y2H, multiple orthogonal experiments","pmids":["11046135"],"is_preprint":false},{"year":2000,"finding":"ERK5 and ERK2 cooperate to activate NF-κB and induce cell transformation; the MEK5-ERK5 pathway is sufficient to activate NF-κB and p90 RSK, and ERK5 is required for NF-κB activation by RafBXB.","method":"Focus formation assay, reporter assay, dominant-negative expression, co-expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and dominant-negative genetics with defined cellular phenotype, single lab","pmids":["11118448"],"is_preprint":false},{"year":2001,"finding":"The C-terminal domain of ERK5 (containing a nuclear localization signal) is required for MEF2C transcriptional activation via nuclear targeting but not for kinase activation; the N-terminal domain (aa 1-77) mediates cytoplasmic targeting; aa 78-139 is required for MEK5 association; aa 140-406 is necessary for oligomerization. Mouse ERK5 splice variants mERK5b and mERK5c act as dominant-negative inhibitors of ERK5a kinase activity.","method":"Domain deletion/mutagenesis, kinase assays, reporter assays, subcellular localization (microscopy), co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with functional readouts (kinase, transcription, localization) in single rigorous study","pmids":["11139578"],"is_preprint":false},{"year":2001,"finding":"BMK1 physically interacts with and phosphorylates serum- and glucocorticoid-inducible kinase (SGK) at Ser78 during growth factor stimulation; this BMK1-mediated phosphorylation is necessary for SGK activation and for growth factor-induced cell proliferation.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — Y2H plus Co-IP plus in vitro kinase assay with site identification plus functional proliferation readout","pmids":["11254654"],"is_preprint":false},{"year":2001,"finding":"H2O2-induced BMK1 activation in PC12 cells is mediated by c-Src (blocked by herbimycin A, PP2, and kinase-inactive Src transfection), leading to enhanced MEF2C DNA-binding activity; BMK1 pathway inhibition increases H2O2-induced cell death.","method":"Kinase activity assay, pharmacological inhibitors, dominant-negative transfection, EMSA, cell viability assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary inhibitor and genetic approaches in single lab","pmids":["11782488"],"is_preprint":false},{"year":2001,"finding":"BMK1 is activated via RET tyrosine kinase signaling through phosphotyrosine 1062; GDNF activates BMK1 through RET-Y1062, and MEN2A RET mutation constitutively activates BMK1; this activation is not blocked by PI3K or RAS/MEK1 inhibitors, suggesting a distinct pathway from canonical Ras signaling.","method":"Site-directed mutagenesis (Y1062F), kinase assay, pharmacological inhibitors, reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus kinase assay plus reporter assay, single lab","pmids":["11237712"],"is_preprint":false},{"year":2001,"finding":"MKK5/ERK5 pathway activation by EGF occurs after ERK1/2 activation in HeLa cells; the classical MAPK cascade exerts negative feedback control over the MKK5/ERK5 pathway; ERK5 is not a significant activator of MAPK-activated protein kinase-1/RSK in HeLa cells (negative finding).","method":"Phospho-specific antibodies, pharmacological inhibitors (U0126, PD184352) at different concentrations","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous phosphorylation measured with specific antibodies, multiple inhibitor concentrations, single lab","pmids":["11478941"],"is_preprint":false},{"year":2002,"finding":"BMK1 activation protects endothelial cells from apoptosis; constitutively active MEK5 activates BMK1 and inhibits caspase-3 activity and apoptosis; BMK1 phosphorylates Bad on Ser112 and Ser136 independently of Akt, PKA, or p90RSK; dominant-negative BMK1 stimulates apoptosis and reduces Bad phosphorylation.","method":"Overexpression of CA-MEK5 and DN-BMK1, MTT assay, caspase-3 assay, phospho-Bad immunoblot, kinase assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary gain- and loss-of-function experiments with defined molecular readouts, replicated across conditions","pmids":["14670836"],"is_preprint":false},{"year":2003,"finding":"WNK1 activates ERK5 through MEKK2 and MEKK3; WNK1 phosphorylates both MEKK2 and MEKK3 in vitro and activates MEKK3 in cells; MEKK2/MEKK3 co-immunoprecipitate with endogenous WNK1; ERK5 activation by EGF is attenuated by WNK1 siRNA knockdown, placing WNK1 upstream of MEKK2/3 in the ERK5 pathway.","method":"Co-immunoprecipitation, in vitro kinase assay, dominant-negative expression, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP plus in vitro kinase assay plus dominant-negative plus siRNA, multiple orthogonal methods","pmids":["14681216"],"is_preprint":false},{"year":2003,"finding":"MEK5beta (short splice variant) inhibits EGF-induced BMK1 activation and MEK5alpha-induced MEF2 transcriptional activity; MEK5beta co-immunoprecipitates with BMK1 and competitively prevents MEK5alpha-BMK1 association, explaining its dominant-negative behavior.","method":"Co-immunoprecipitation, kinase assay, reporter assay, overexpression of splice variants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus kinase and reporter assays, mechanism defined, single lab","pmids":["14583600"],"is_preprint":false},{"year":2004,"finding":"Conditional genetic ablation of BMK1 in adult mice leads to lethality with vascular leakage, endothelial cell rounding, misalignment, and apoptosis; endothelial-specific BMK1 KO recapitulates cardiovascular defects; in vitro BMK1 removal causes endothelial death partially via deregulation of the direct substrate MEF2C. Cardiomyocyte-specific BMK1 KO mice develop normally.","method":"Conditional knockout mice (Mx1-Cre), histology, in vitro siRNA/knockdown, MEF2C reporter assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with tissue-specific phenotyping and in vitro mechanistic follow-up identifying MEF2C as direct substrate","pmids":["15085193"],"is_preprint":false},{"year":2005,"finding":"BMK1/ERK5 negatively regulates HIF1α by promoting its ubiquitination and proteasomal degradation; constitutively active MEK5 reduces HIF1α protein levels and inhibits HIF1α-driven angiogenesis and EC migration; dominant-negative BMK1 enhances HIF1α activity.","method":"Reporter assay, immunoblot, ubiquitination inhibitors, overexpression of CA-MEK5 and DN-BMK1, Matrigel angiogenesis assay, EC migration assay","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with gain/loss of function, single lab","pmids":["15879308"],"is_preprint":false},{"year":2006,"finding":"ERK5 binds to and phosphorylates p90 RSK in vitro, causing RSK activation; the common docking (CD) domain of ERK5 and the D domain of RSK mediate their association; the large C-terminal domain of ERK5 is not required for RSK binding or activation; activation of ERK5 weakens its binding to RSK suggesting RSK is released upon ERK5 activation.","method":"Co-immunoprecipitation, in vitro kinase assay, domain deletion analysis","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus Co-IP plus domain mapping, single lab","pmids":["16626623"],"is_preprint":false},{"year":2008,"finding":"ERK5 controls EGF-induced Slug expression and keratinocyte migration; Erk5 pathway inhibition blocks keratinocyte migration and alters desmosome organization; shRNA knockdown of Erk5 reduces motility and Slug induction in response to EGF.","method":"shRNA knockdown, pharmacological inhibition, wound healing assay, immunofluorescence","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with defined phenotypic and molecular readouts, single lab","pmids":["18716062"],"is_preprint":false},{"year":2008,"finding":"In endothelial cells, MEK5-BMK1 (but not MEK1-ERK1/2) signaling mediates flow-induced inhibition of TNF-α-activated JNK; selective MEK5 inhibitor BIX02188 completely reverses the flow-mediated inhibition of JNK activation.","method":"Pharmacological inhibitors (PD184352 at selective concentrations, BIX02188), kinase assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective pharmacological dissection with two inhibitors, single lab","pmids":["18358237"],"is_preprint":false},{"year":2008,"finding":"ERK5/BMK1 is required for optimal CSF-1-induced macrophage proliferation; ERK5 activation by CSF-1 is Src family kinase-dependent; following CSF-1 stimulation, active ERK5 translocates from cytosol to nucleus; ERK5 siRNA reduces c-Jun phosphorylation/expression and increases p27 expression.","method":"siRNA knockdown, kinase assay, nuclear fractionation, immunoblot, DNA synthesis assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined molecular phenotype and subcellular localization, single lab","pmids":["18322228"],"is_preprint":false},{"year":2009,"finding":"Constitutive MEK5/ERK5 activation strongly inhibits endothelial cell migration, increases focal contact number and actin stress fibers, reduces p130Cas expression (a key mediator of directed migration), and decreases focal contact turnover.","method":"Retroviral gene transfer (CA-MEK5), cell migration assay, immunofluorescence, immunoblot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined molecular and cellular phenotype, single lab","pmids":["19605361"],"is_preprint":false},{"year":2009,"finding":"ERK1/2, but not ERK5, is necessary and sufficient for c-Fos phosphorylation and transcriptional activation; c-Fos expression is normal in ERK5−/− cells; however, ERK5−/− cells are defective for c-Jun expression, which is rescued by ERK5 re-expression.","method":"Conditional kinase activation, selective MEK inhibitors, ERK5-null fibroblasts, reporter assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout cells plus selective pharmacological inhibitors plus conditional kinases, multiple orthogonal approaches","pmids":["19249353"],"is_preprint":false},{"year":2010,"finding":"CDK1 co-precipitates with ERK5 in mitotic cells and its activity is required for ERK5 phosphorylation at multiple C-terminal sites during mitosis (a second MEK5-independent phosphorylation pathway); mitotic C-terminal phosphorylation controls ERK5 nuclear-cytoplasmic shuttling and transcriptional activity.","method":"Co-immunoprecipitation, CDK1 inhibitor (RO3306), phosphorylation site mapping, subcellular fractionation, reporter assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus pharmacological inhibition plus localization analysis, single lab","pmids":["20736311"],"is_preprint":false},{"year":2010,"finding":"BMK1 interacts with PML isoform IV and phosphorylates PML, inhibiting its tumor-suppressor function and PML-dependent p21 activation; the BMK1 inhibitor XMD8-92 blocks tumor cell proliferation in vitro and inhibits tumor growth in vivo by ~95%.","method":"Co-immunoprecipitation, in vitro kinase assay, cell proliferation assay, xenograft mouse model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP plus in vitro kinase assay plus in vivo xenograft with pharmacological inhibitor, multiple orthogonal methods","pmids":["20832753"],"is_preprint":false},{"year":2012,"finding":"Activated BMK1 preferentially associates with PML isoform IV and disrupts PML-MDM2 interaction, suppressing p53 activation; BMK1 deactivation combined with doxorubicin synergistically enhances MDM2 nucleolar sequestration and PML-mediated p53 upregulation.","method":"Co-immunoprecipitation, immunoblot, reporter assay, in vitro and in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional signaling readouts, single lab","pmids":["22869143"],"is_preprint":false},{"year":2012,"finding":"BMK1 signaling suppresses EMT: BMK1 elevation augments E-cadherin-mediated cell-cell adhesion and reduces mesenchymal markers, while BMK1 silencing promotes Snail nuclear accumulation via Akt/GSK3β signaling activated through DEPTOR-mediated mTOR inhibition.","method":"siRNA knockdown, overexpression, immunoblot, cell adhesion/motility assay, in vivo metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with molecular pathway delineation, single lab","pmids":["22282661"],"is_preprint":false},{"year":2013,"finding":"X-ray crystal structure of ERK5 (MAPK7) kinase domain in complex with a benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one inhibitor was determined; specific residue differences in the ATP-binding site distinguish ERK5 from ERK1/2, p38, and JNKs, providing a structural basis for inhibitor selectivity.","method":"X-ray crystallography","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determination, foundational structural data for ERK5 kinase domain","pmids":["23656407"],"is_preprint":false},{"year":2013,"finding":"ERK5 is degraded via the ubiquitin-proteasome system in a process mediated by the tumor suppressor VHL through a prolyl hydroxylation-dependent mechanism; ERK5 knockdown in pVHL-negative cell lines decreases proliferation and migration.","method":"Transient transfection, siRNA knockdown, immunoblot, proteasome inhibitors","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — VHL-dependent degradation established with proteasome inhibitors and functional cell assays, single lab","pmids":["23730213"],"is_preprint":false},{"year":2014,"finding":"ALK activates ERK5 through a PI3K-AKT-MEKK3-MEK5 pathway; ALK-induced MYCN transcription and neuroblastoma cell proliferation require ERK5; pharmacological or siRNA inhibition of ERK5 suppresses neuroblastoma cell proliferation and enhances the anti-tumor efficacy of the ALK inhibitor crizotinib.","method":"Pharmacological inhibitors, siRNA knockdown, reporter assay, xenograft models","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway delineation using multiple inhibitors plus siRNA plus in vivo xenograft validation","pmids":["25351247"],"is_preprint":false},{"year":2014,"finding":"ERK5 activation in macrophages promotes efferocytosis; macrophage-specific ERK5-null mice show reduced efferocytosis and accelerated atherosclerotic plaque formation on a hypercholesterolemic background.","method":"Conditional macrophage-specific ERK5 knockout mice, efferocytosis assays, atherosclerosis model","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic KO with defined functional phenotype and in vivo disease model","pmids":["25001623"],"is_preprint":false},{"year":2014,"finding":"ERK5 activation inhibits endothelial cell migration via a KLF2-dependent downregulation of PAK1 mRNA and protein; KLF2 (but not KLF4) knockdown prevents ERK5-mediated PAK1 repression and restores migration capacity.","method":"Constitutively active MEK5 expression, siRNA knockdown (KLF2, KLF4, PAK1), qRT-PCR, immunoblot, migration assay","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with specific siRNA rescue, single lab","pmids":["25388666"],"is_preprint":false},{"year":2015,"finding":"Pak2 (but not Pak1) signals through the Bmk1/Erk5 pathway to regulate endothelial development and function; endothelial Pak2 depletion causes embryonic lethality and adult vascular permeability; these defects are mediated through the Bmk1/Erk5 pathway.","method":"Conditional knockout mice, epistasis experiments, in vitro kinase assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis using conditional KO mice with functional phenotypic readouts, single lab","pmids":["26391956"],"is_preprint":false},{"year":2015,"finding":"Phosphorylation of ERK5 at Thr732 by ERK1/2 (downstream of oncogenic Ras or growth factors) promotes ERK5 nuclear localization and MEF2C transcriptional activity, independently of TEY motif phosphorylation; ERK5-T732A mutant remains cytosolic under basal conditions.","method":"Site-directed mutagenesis (T732A, T732E), pharmacological inhibitors, subcellular fractionation, reporter assay, immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus localization studies plus reporter assays in single lab","pmids":["25689862"],"is_preprint":false},{"year":2016,"finding":"ERK5 kinase inhibitors paradoxically activate ERK5 transcriptional activity through its C-terminal TAD domain; inhibitor binding to the kinase domain promotes conformational changes that drive nuclear translocation and gene transcription; kinase-active drug-resistant ERK5 mutants confirmed that direct inhibitor binding to the kinase domain is required for paradoxical transcriptional activation.","method":"Drug-resistant kinase mutants, nuclear localization assay, reporter assay, kinase inhibitor panel","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — drug-resistant mutant approach plus multiple functional assays, mechanistically rigorous, published in Nature Communications","pmids":["32170057"],"is_preprint":false},{"year":2016,"finding":"Selective ERK5 kinase inhibitors (lacking bromodomain activity) have no antiinflammatory or antiproliferative activity, while previously reported ERK5 inhibitors derive their efficacy from off-target bromodomain inhibition; ERK5 genetic deletion/depletion phenotypes likely arise from non-catalytic (kinase-independent) functions of ERK5.","method":"Selective inhibitor synthesis and characterization, KINOMEscan, bromodomain binding assays, cell proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous selectivity profiling with orthogonal assays demonstrating off-target activity of prior inhibitors","pmids":["27679845"],"is_preprint":false},{"year":2016,"finding":"Loss of Erk1/2 in intestinal epithelial cells results in supraphysiological ERK5 pathway activity; targeting both ERK1/2 and ERK5 more effectively suppresses cell proliferation than targeting either alone in intestinal organoids and CRC lines, demonstrating ERK5 as a bypass route for proliferation upon ERK1/2 abrogation.","method":"Conditional Erk1/2 knockout mice, intestinal organoids, siRNA, pharmacological inhibitors","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus pharmacological epistasis plus organoid models, multiple orthogonal approaches","pmids":["27187615"],"is_preprint":false},{"year":2017,"finding":"YAP promotes myogenic differentiation via the MEK5-ERK5 pathway through a Src/c-Abl/MEKK3 cascade; YAP physically interacts with MEKK3 (via PPGY motif at aa 178-181) and ERK5 as shown by co-immunoprecipitation; MEKK3 Y181F mutation inhibits MEK5/ERK5 activation and myogenic differentiation.","method":"Co-immunoprecipitation, site-directed mutagenesis, pharmacological inhibitors, Western blot, differentiation assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis plus functional differentiation assays, single lab","pmids":["28356344"],"is_preprint":false},{"year":2018,"finding":"Oncogenic BRAF positively regulates ERK5 expression, phosphorylation, and nuclear localization; both ERK5 kinase and transcriptional transactivation activities are enhanced by BRAF; combined inhibition of MEK5 and BRAFV600E is required to decrease nuclear ERK5, which is critical for cell proliferation.","method":"siRNA knockdown, pharmacological inhibitors, immunofluorescence (nuclear ERK5), colony formation assay, xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological dissection with subcellular localization readout and in vivo validation, single lab","pmids":["29483645"],"is_preprint":false},{"year":2020,"finding":"ERK5 SUMOylation at Lys6/Lys22 is required for nuclear translocation and cancer cell proliferation; MEK5 activation or Cdc37 overexpression induces SUMO-2 modification of ERK5; SUMO site mutation (K6R/K22R) abolishes nuclear ERK5 localization; SENP2 overexpression abolishes endogenous ERK5 nuclear localization in response to EGF.","method":"SUMO site mutagenesis, immunofluorescence, immunoblot, cell proliferation assay, SENP2 overexpression","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus localization plus functional proliferation assays, single lab","pmids":["32209980"],"is_preprint":false},{"year":2022,"finding":"Shear stress activates PIEZO1, causing calcium influx that activates CaMKII, which interacts with and activates MEKK3 to promote MEKK3/MEK5/ERK5 signaling and ultimately KLF2/4 transcription; endothelial-specific Piezo1 deletion reduces KLF2/4 expression in vivo.","method":"Conditional endothelial Piezo1 KO mice, co-immunoprecipitation (CaMKII-MEKK3), pharmacological inhibitors, shear stress assays, qRT-PCR","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO plus Co-IP plus pathway inhibition, single lab","pmids":["35883633"],"is_preprint":false},{"year":2023,"finding":"ERK5 S496 phosphorylation mediates senescence-associated secretory phenotype (SASP) and senescence-associated stemness in macrophages by upregulating AHR; ERK5 S496 phosphorylation induces NRF2 SUMOylation at K518, inhibiting NRF2 transcriptional activity without altering ERK5 catalytic activity; S496A knock-in mice are protected from atherosclerosis.","method":"CRISPR/Cas9 knock-in mouse (S496A), RNA sequencing, imaging mass cytometry, SUMOylation assay, metabolic flux analysis, pharmacological ERK5 inhibitors","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1 / Strong — knock-in mouse model plus multiple orthogonal biochemical assays identifying specific phosphorylation site mechanism","pmids":["37264926"],"is_preprint":false}],"current_model":"MAPK7/ERK5/BMK1 is a dual-function protein containing an N-terminal kinase domain (activated by MEK5 via dual TEY phosphorylation, with upstream inputs from MEKK2/3 and WNK1) and a unique C-terminal domain harboring transcriptional activation, nuclear localization, and MEF2-interaction modules; activated ERK5 translocates to the nucleus (regulated by C-terminal autophosphorylation, CDK1-mediated mitotic phosphorylation, SUMOylation at K6/K22, and ERK1/2-mediated Thr732 phosphorylation) where it directly phosphorylates and coactivates MEF2 transcription factors, phosphorylates Sap1a, and engages NF-κB signaling, while in the cytoplasm it phosphorylates substrates including SGK (Ser78), Bad (Ser112/136), PML, and p90 RSK to promote cell survival, proliferation, and suppress apoptosis and EMT; paradoxically, ERK5 kinase inhibitors can activate ERK5 transcriptional activity through conformational changes in the kinase domain, and many reported phenotypes attributed to ERK5 kinase activity may reflect non-catalytic functions of the protein."},"narrative":{"mechanistic_narrative":"MAPK7 (ERK5/BMK1) is a dual-function MAP kinase that couples growth-factor, mechanical, and oxidative-stress signaling to transcriptional programs governing cell proliferation, survival, and vascular/endothelial homeostasis [PMID:7646528, PMID:9790194, PMID:15085193]. It carries an N-terminal kinase domain bearing a TEY dual-phosphorylation motif and a distinctive large C-terminal region that contains a transcriptional activation domain, a nuclear localization signal, and a MEF2-interaction module, the latter required for ERK5 to bind, phosphorylate, and coactivate MEF2 transcription factors [PMID:7646528, PMID:9753748, PMID:11046135, PMID:11139578]. Activation flows through a dedicated module in which MEKK2 or MEKK3 (cell-type-specifically) feed into MEK5, which dually phosphorylates ERK5, with WNK1 acting upstream of the MEKKs and diverse inputs (EGF/NGF receptor tyrosine kinases, RET-Y1062, ALK via PI3K-AKT, oncogenic BRAF, fluid shear stress via PIEZO1/CaMKII, and H2O2 via c-Src) converging on this cascade [PMID:9790194, PMID:10593883, PMID:11073940, PMID:11237712, PMID:14681216, PMID:25351247, PMID:29483645, PMID:35883633]. Nuclear translocation and transcriptional output are gated by multiple post-translational events distinct from TEY phosphorylation: C-terminal autophosphorylation, CDK1-mediated mitotic phosphorylation, SUMOylation at Lys6/Lys22, and ERK1/2-mediated Thr732 phosphorylation [PMID:11139578, PMID:20736311, PMID:25689862, PMID:32209980]. In addition to MEF2 and the Ets factor Sap1a, ERK5 phosphorylates SGK (Ser78), Bad (Ser112/136), PML, and p90 RSK, and engages NF-κB, promoting proliferation and survival while inhibiting apoptosis [PMID:10473620, PMID:11118448, PMID:11254654, PMID:14670836, PMID:16626623, PMID:20832753]. Genetic ablation establishes ERK5 as essential for endothelial integrity, where its loss causes vascular leakage, endothelial apoptosis, and lethality partly through deregulation of MEF2C [PMID:15085193], and it drives macrophage efferocytosis, EMT suppression, and tumor proliferation [PMID:20832753, PMID:22282661, PMID:25001623]. A critical reinterpretation of this biology comes from work showing that ERK5 kinase inhibitors paradoxically activate its C-terminal transcriptional activity through kinase-domain conformational changes, that several reported ERK5 inhibitors act through off-target bromodomain inhibition, and that many genetic-loss phenotypes likely reflect non-catalytic functions of the protein [PMID:32170057, PMID:27679845].","teleology":[{"year":1995,"claim":"Establishing that ERK5/BMK1 was a genuinely distinct MAP kinase rather than an ERK1/2 paralog set the stage for asking what unique signals it transduces.","evidence":"Molecular cloning and sequence analysis of an 816-residue kinase with a TEY motif but a divergent C-terminus and loop-12","pmids":["7646528"],"confidence":"Medium","gaps":["No upstream activator or substrate identified","Function of the unique C-terminal domain unknown"]},{"year":1996,"claim":"Identifying selective activation by H2O2, distinct from ERK1/2 stimuli, provided the first physiological context (oxidative/vascular stress) for ERK5 signaling.","evidence":"Kinase activity assays with multiple stimuli and calcium chelation in vascular smooth muscle cells","pmids":["8663194"],"confidence":"Medium","gaps":["Upstream kinase cascade not defined","Downstream effectors unknown"]},{"year":1998,"claim":"Linking ERK5 to MEF2 and to EGF-driven proliferation defined its two core outputs: direct transcription-factor coactivation and cell-cycle entry.","evidence":"Y2H, GST pulldown, Co-IP, in vitro kinase and reporter assays (MEF2); dominant-negative BMK1 with cell-cycle/BrdU analysis (EGF proliferation)","pmids":["9753748","9790194"],"confidence":"High","gaps":["Upstream activating kinases for MEK5 not yet identified","Mechanism of nuclear targeting unresolved"]},{"year":1999,"claim":"Defining the MEKK3-MEK5-ERK5 cascade and a second substrate (Sap1a) built the canonical three-tier module and broadened its transcriptional reach to SRE/c-Fos.","evidence":"Y2H and reciprocal Co-IP for MEKK3-MEK5; dominant-negative genetics, in vitro kinase and reporter assays for Sap1a; mechanistic dissection of shear-stress activation","pmids":["10593883","10473620","9867822"],"confidence":"High","gaps":["Cell-type specificity of MEKK usage not yet appreciated","Upstream input to MEKK3 undefined"]},{"year":2000,"claim":"Mapping the C-terminal TAD, NLS, MEF2-interaction and oligomerization modules, plus an alternative MEKK2 input and an NF-κB/RSK link, established the molecular architecture underlying ERK5's dual kinase/transcriptional nature.","evidence":"Systematic domain deletion/mutagenesis with kinase, reporter and localization readouts; Y2H/Co-IP for MEKK2; reporter and focus-formation assays for NF-κB","pmids":["11046135","11139578","11073940","11118448"],"confidence":"High","gaps":["Signals controlling nuclear translocation only partly defined","Direct NF-κB substrate not identified"]},{"year":2001,"claim":"Identifying SGK (Ser78) and Bad-adjacent survival signaling, plus RET-Y1062 and redox/c-Src inputs, connected ERK5 to growth-factor proliferation and cell-survival programs through specific phospho-substrates and additional receptor inputs.","evidence":"Y2H, Co-IP, in vitro kinase assays with site mapping (SGK); mutagenesis and kinase/reporter assays (RET); inhibitor and dominant-negative dissection (c-Src/MEF2C); negative-feedback mapping by ERK1/2","pmids":["11254654","11237712","11782488","11478941"],"confidence":"Medium","gaps":["In vivo relevance of each substrate not established","Hierarchy among multiple receptor inputs unclear"]},{"year":2002,"claim":"Showing ERK5 phosphorylates Bad at Ser112/136 independently of Akt/PKA/RSK and protects endothelial cells from apoptosis defined a direct anti-apoptotic mechanism.","evidence":"CA-MEK5 and DN-BMK1 overexpression, caspase-3 and MTT assays, phospho-Bad immunoblot, kinase assay","pmids":["14670836"],"confidence":"High","gaps":["Direct vs indirect Bad phosphorylation in vivo not resolved"]},{"year":2003,"claim":"Placing WNK1 upstream of MEKK2/3 and defining the dominant-negative MEK5beta splice variant clarified pathway regulation at the input and adaptor levels.","evidence":"Co-IP, in vitro kinase assay, dominant-negative and siRNA (WNK1); Co-IP and competition assays (MEK5beta)","pmids":["14681216","14583600"],"confidence":"High","gaps":["Physiological stimuli engaging WNK1-ERK5 not defined","Tissue distribution of MEK5beta unknown"]},{"year":2004,"claim":"Conditional knockout established ERK5 as essential in vivo for endothelial integrity and vascular survival, acting partly through MEF2C, anchoring the pathway in cardiovascular biology.","evidence":"Mx1-Cre and endothelial-specific knockout mice with histology; in vitro knockdown and MEF2C reporter assay","pmids":["15085193"],"confidence":"High","gaps":["Catalytic vs non-catalytic contribution to phenotype not dissected","Full set of essential transcriptional targets unknown"]},{"year":2005,"claim":"Identifying ERK5-driven HIF1alpha degradation and a direct p90 RSK interaction extended ERK5 control to angiogenic and downstream-kinase signaling.","evidence":"Reporter, immunoblot, ubiquitination and angiogenesis/migration assays (HIF1alpha); Co-IP, in vitro kinase and domain mapping (RSK)","pmids":["15879308","16626623"],"confidence":"Medium","gaps":["Mechanism by which ERK5 promotes HIF1alpha ubiquitination unclear","RSK activation by ERK5 contradicts prior negative finding in HeLa"]},{"year":2008,"claim":"Roles in keratinocyte migration/Slug, macrophage proliferation with nuclear translocation, and flow-mediated JNK suppression broadened ERK5's cellular repertoire beyond endothelium.","evidence":"shRNA and wound healing (keratinocytes); siRNA, fractionation and DNA synthesis (macrophages); selective MEK5 inhibitor BIX02188 (JNK suppression)","pmids":["18716062","18322228","18358237"],"confidence":"Medium","gaps":["Direct transcriptional targets in each context not defined","Catalytic dependence not tested with selective tools"]},{"year":2009,"claim":"Genetic dissection separated ERK1/2 (c-Fos) from ERK5 (c-Jun) outputs and revealed ERK5-controlled inhibition of endothelial migration via p130Cas, refining the non-redundant transcriptional functions of ERK5.","evidence":"ERK5-null fibroblasts, selective MEK inhibitors and conditional kinases (c-Fos/c-Jun); CA-MEK5 retroviral transfer and migration/immunofluorescence (p130Cas)","pmids":["19249353","19605361"],"confidence":"High","gaps":["Mechanism of c-Jun control by ERK5 not fully resolved"]},{"year":2010,"claim":"Discovering CDK1-mediated mitotic phosphorylation and the PML interaction established a MEK5-independent regulatory route and a tumor-relevant substrate, with XMD8-92 validating ERK5 as an anti-cancer target.","evidence":"Co-IP, CDK1 inhibitor, phospho-site mapping and fractionation (mitotic); Co-IP, in vitro kinase, proliferation and xenograft assays (PML/XMD8-92)","pmids":["20736311","20832753"],"confidence":"High","gaps":["XMD8-92 specificity later questioned","Functional consequence of mitotic phosphorylation incompletely defined"]},{"year":2012,"claim":"Linking ERK5-PML to p53 suppression and defining ERK5 suppression of EMT positioned the kinase as both tumor-promoting (via PML/p53) and metastasis-restraining (via E-cadherin/Snail).","evidence":"Co-IP, reporter and tumor models (PML-MDM2-p53); siRNA/overexpression with adhesion, motility and metastasis assays (EMT)","pmids":["22869143","22282661"],"confidence":"Medium","gaps":["Context determining pro- vs anti-tumor role unclear","Direct PML phosphosites linking to p53 axis not mapped"]},{"year":2013,"claim":"Solving the kinase-domain crystal structure and defining VHL-mediated degradation provided structural and stability-control foundations for the pathway.","evidence":"X-ray crystallography of the kinase domain with a selective inhibitor; transfection, siRNA, proteasome inhibitors (VHL degradation)","pmids":["23656407","23730213"],"confidence":"High","gaps":["No structure of the regulatory C-terminal domain","Prolyl-hydroxylation/VHL recognition motif on ERK5 not defined"]},{"year":2014,"claim":"ALK-PI3K-MEKK3-MEK5-ERK5 driving MYCN in neuroblastoma, KLF2-dependent migration control, and a macrophage efferocytosis/atherosclerosis role expanded ERK5 into oncology and cardiovascular disease as a therapeutic node.","evidence":"Inhibitors, siRNA, reporter and xenograft (ALK/MYCN); CA-MEK5 with KLF2/PAK1 knockdown (migration); macrophage-specific KO with efferocytosis and atherosclerosis models","pmids":["25351247","25388666","25001623"],"confidence":"High","gaps":["Catalytic dependence of these phenotypes not tested with clean tools","How ERK5 selects MYCN/KLF2 programs unclear"]},{"year":2015,"claim":"Mapping Thr732 phosphorylation by ERK1/2 and Pak2-dependent endothelial signaling defined additional activation/localization inputs feeding ERK5 nuclear function and vascular development.","evidence":"T732A/T732E mutagenesis, fractionation, reporter and immunofluorescence (Thr732); conditional KO and epistasis (Pak2)","pmids":["25689862","26391956"],"confidence":"Medium","gaps":["Relative contribution of Thr732 vs TEY phosphorylation in vivo unclear","Mechanism linking Pak2 to the cascade incompletely defined"]},{"year":2016,"claim":"The discovery that kinase inhibitors paradoxically activate ERK5 transcription, that prior inhibitors acted via off-target bromodomain inhibition, and that ERK1/2 loss unmasks ERK5 as a proliferation bypass forced a major reinterpretation: many ERK5 phenotypes reflect non-catalytic functions or tool artifacts.","evidence":"Drug-resistant kinase mutants with localization/reporter assays; selective inhibitor synthesis with KINOMEscan and bromodomain profiling; Erk1/2 conditional KO with organoids and CRC lines","pmids":["32170057","27679845","27187615"],"confidence":"High","gaps":["Which catalytic substrates retain physiological relevance unresolved","Mechanism of paradoxical TAD activation by inhibitors not fully structural"]},{"year":2017,"claim":"Defining YAP-MEKK3-MEK5-ERK5 in myogenic differentiation extended the pathway into developmental/mechanotransduction biology with a physical YAP-MEKK3 interaction.","evidence":"Co-IP, PPGY-motif and MEKK3 Y181F mutagenesis, inhibitors, differentiation assays","pmids":["28356344"],"confidence":"Medium","gaps":["ERK5 transcriptional targets in myogenesis not defined","Catalytic dependence not isolated"]},{"year":2018,"claim":"Showing oncogenic BRAF enhances both ERK5 expression and nuclear localization, requiring combined MEK5/BRAF inhibition, reinforced ERK5 as a co-targetable node in RAF-driven cancers.","evidence":"siRNA, inhibitors, nuclear-ERK5 immunofluorescence, colony formation and xenograft","pmids":["29483645"],"confidence":"Medium","gaps":["Mechanism by which BRAF drives ERK5 nuclear localization unclear"]},{"year":2020,"claim":"Establishing SUMOylation at Lys6/Lys22 as required for nuclear translocation and proliferation added a defined PTM controlling ERK5's transcriptional access.","evidence":"SUMO-site mutagenesis (K6R/K22R), immunofluorescence, immunoblot, SENP2 overexpression, proliferation assays","pmids":["32209980"],"confidence":"Medium","gaps":["SUMO E3 ligase for ERK5 not identified","Interplay with other nuclear-targeting PTMs unresolved"]},{"year":2022,"claim":"Defining the PIEZO1-calcium-CaMKII-MEKK3 input clarified how mechanical shear stress is transduced to ERK5-driven KLF2/4 transcription in endothelium.","evidence":"Endothelial Piezo1 KO mice, CaMKII-MEKK3 Co-IP, inhibitors, shear-stress assays, qRT-PCR","pmids":["35883633"],"confidence":"Medium","gaps":["Direct CaMKII phosphosite on MEKK3 not mapped","Catalytic vs scaffold role of ERK5 in KLF2/4 induction unclear"]},{"year":2023,"claim":"Identifying ERK5 S496 phosphorylation as driving SASP/senescence via NRF2 SUMOylation without altering catalytic activity provided direct in vivo proof of a kinase-independent, atheroprotective-relevant ERK5 function.","evidence":"S496A CRISPR knock-in mice, RNA-seq, imaging mass cytometry, SUMOylation and metabolic-flux assays, ERK5 inhibitors","pmids":["37264926"],"confidence":"High","gaps":["Kinase responsible for S496 phosphorylation not defined","Generality of non-catalytic mechanism across other phenotypes unknown"]},{"year":null,"claim":"It remains unresolved which ERK5 phenotypes depend on its catalytic kinase activity versus non-catalytic/scaffold and transcriptional functions, and the structure-function basis of its regulatory C-terminal domain is undefined.","evidence":"No direct experimental resolution in the available corpus","pmids":[],"confidence":"Low","gaps":["Catalytic vs non-catalytic contributions not systematically separated for most substrates","No structure of the C-terminal TAD/NLS/MEF2-interaction region","Physiological substrate set under selective, on-target inhibition unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,11,15,20,27]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,11,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,10,37]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,30]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,23,26,36,42]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,23,36]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,7,16,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression 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The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras-independent and MAP2K5-dependent pathway. As part of the MAPK/ERK signaling pathway, acts as a negative regulator of apoptosis in cardiomyocytes via interaction with STUB1/CHIP and promotion of STUB1-mediated ubiquitination and degradation of ICER-type isoforms of CREM (By similarity). May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction","subcellular_location":"Cytoplasm; Nucleus; Nucleus, PML body","url":"https://www.uniprot.org/uniprotkb/Q13164/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAPK7","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAPK7","total_profiled":1310},"omim":[{"mim_id":"612117","title":"MICRO RNA 143; MIR143","url":"https://www.omim.org/entry/612117"},{"mim_id":"609487","title":"MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 2; MAP3K2","url":"https://www.omim.org/entry/609487"},{"mim_id":"609479","title":"MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 20; MAP3K20","url":"https://www.omim.org/entry/609479"},{"mim_id":"604439","title":"GRB2-ASSOCIATED BINDING PROTEIN 1; GAB1","url":"https://www.omim.org/entry/604439"},{"mim_id":"602521","title":"MITOGEN-ACTIVATED PROTEIN KINASE 7; MAPK7","url":"https://www.omim.org/entry/602521"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAPK7"},"hgnc":{"alias_symbol":["BMK1","ERK5"],"prev_symbol":["PRKM7"]},"alphafold":{"accession":"Q13164","domains":[{"cath_id":"3.30.200.20","chopping":"43-139_373-378","consensus_level":"medium","plddt":88.9882,"start":43,"end":378},{"cath_id":"1.10.510.10","chopping":"140-358","consensus_level":"medium","plddt":92.2746,"start":140,"end":358}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13164","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13164-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13164-F1-predicted_aligned_error_v6.png","plddt_mean":65.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAPK7","jax_strain_url":"https://www.jax.org/strain/search?query=MAPK7"},"sequence":{"accession":"Q13164","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13164.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13164/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13164"}},"corpus_meta":[{"pmid":"10473620","id":"PMC_10473620","title":"Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. 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ERK5 phosphorylates MEF2 in vitro and enhances MEF2 transactivation capacity when co-expressed.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, in vitro kinase assay, reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (Y2H, GST pulldown, Co-IP, in vitro kinase assay, reporter assay) in single study\",\n      \"pmids\": [\"9753748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"EGF-mediated activation of BMK1/ERK5 occurs independently of Ras and requires MEK5; expression of dominant-negative BMK1 blocks EGF-induced cell proliferation and prevents S-phase entry, establishing BMK1 as required for EGF-induced cell proliferation.\",\n      \"method\": \"Dominant-negative expression, cell cycle analysis, BrdU incorporation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dominant-negative approach with defined cell-cycle phenotype, published in Nature with multiple complementary experiments\",\n      \"pmids\": [\"9790194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ERK5 is activated by EGF and NGF downstream of receptor tyrosine kinases via a Ras-dependent pathway; ERK5 phosphorylates the Ets-domain transcription factor Sap1a (but not Elk1) in vitro and in cells, and the ERK5 pathway mediates serum-induced c-Fos expression and serum response element transcription via Sap1a.\",\n      \"method\": \"Dominant-negative expression, reporter assay, in vitro kinase assay, phosphatase inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus reporter assays plus dominant-negative genetics in multiple cell contexts\",\n      \"pmids\": [\"10473620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MEKK3 physically interacts with MEK5 (identified by yeast two-hybrid, confirmed by co-immunoprecipitation) and, as a dominant-active form, stimulates BMK1 activity through MEK5; endogenous MEKK3 activity is required for growth factor-mediated BMK1 activation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, dominant-active/dominant-negative expression, kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Y2H plus reciprocal Co-IP plus functional kinase cascade reconstitution in cells\",\n      \"pmids\": [\"10593883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Fluid shear stress potently activates BMK1/ERK5 in endothelial cells via a mechanism dependent on non-Src tyrosine kinases and intracellular calcium, but not on Src, redox state, NO, PKA, PKC, PKG, CaM kinase, PI3K, or arachidonic acid metabolism.\",\n      \"method\": \"Kinase activity assay, pharmacological inhibitors, overexpression of kinase-inactive c-Src, calcium chelation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase assay with multiple mechanistic dissection experiments, single lab\",\n      \"pmids\": [\"9867822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MEKK2 binds MEK5 (identified by yeast two-hybrid), activates BMK1/ERK5 through MEK5, and this activation is cell-type specific (MEKK3 required in Cos7/HEK293; MEKK2 required in D10 T cells); MEKK2 also interacts with the T cell adapter Lad/RIBP and co-localizes at the T cell-APC contact site.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, dominant-negative expression, kinase assay, co-localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Y2H plus Co-IP plus functional kinase assays plus co-localization across multiple cell types\",\n      \"pmids\": [\"11073940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ERK5 contains a C-terminal transcriptional activation domain (TAD) and a MEF2-interacting domain in its C-terminal half; these domains are required for coactivation of MEF2D, and the MEF2-ERK5 interaction is activation-dependent in vivo and inhibitable by the MEF2 repressor Cabin1.\",\n      \"method\": \"Yeast two-hybrid, reporter assay, domain deletion/mutagenesis, promoter activation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional domain mapping with mutagenesis plus reporter assays plus Y2H, multiple orthogonal experiments\",\n      \"pmids\": [\"11046135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ERK5 and ERK2 cooperate to activate NF-κB and induce cell transformation; the MEK5-ERK5 pathway is sufficient to activate NF-κB and p90 RSK, and ERK5 is required for NF-κB activation by RafBXB.\",\n      \"method\": \"Focus formation assay, reporter assay, dominant-negative expression, co-expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and dominant-negative genetics with defined cellular phenotype, single lab\",\n      \"pmids\": [\"11118448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The C-terminal domain of ERK5 (containing a nuclear localization signal) is required for MEF2C transcriptional activation via nuclear targeting but not for kinase activation; the N-terminal domain (aa 1-77) mediates cytoplasmic targeting; aa 78-139 is required for MEK5 association; aa 140-406 is necessary for oligomerization. Mouse ERK5 splice variants mERK5b and mERK5c act as dominant-negative inhibitors of ERK5a kinase activity.\",\n      \"method\": \"Domain deletion/mutagenesis, kinase assays, reporter assays, subcellular localization (microscopy), co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with functional readouts (kinase, transcription, localization) in single rigorous study\",\n      \"pmids\": [\"11139578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BMK1 physically interacts with and phosphorylates serum- and glucocorticoid-inducible kinase (SGK) at Ser78 during growth factor stimulation; this BMK1-mediated phosphorylation is necessary for SGK activation and for growth factor-induced cell proliferation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Y2H plus Co-IP plus in vitro kinase assay with site identification plus functional proliferation readout\",\n      \"pmids\": [\"11254654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"H2O2-induced BMK1 activation in PC12 cells is mediated by c-Src (blocked by herbimycin A, PP2, and kinase-inactive Src transfection), leading to enhanced MEF2C DNA-binding activity; BMK1 pathway inhibition increases H2O2-induced cell death.\",\n      \"method\": \"Kinase activity assay, pharmacological inhibitors, dominant-negative transfection, EMSA, cell viability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary inhibitor and genetic approaches in single lab\",\n      \"pmids\": [\"11782488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BMK1 is activated via RET tyrosine kinase signaling through phosphotyrosine 1062; GDNF activates BMK1 through RET-Y1062, and MEN2A RET mutation constitutively activates BMK1; this activation is not blocked by PI3K or RAS/MEK1 inhibitors, suggesting a distinct pathway from canonical Ras signaling.\",\n      \"method\": \"Site-directed mutagenesis (Y1062F), kinase assay, pharmacological inhibitors, reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus kinase assay plus reporter assay, single lab\",\n      \"pmids\": [\"11237712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MKK5/ERK5 pathway activation by EGF occurs after ERK1/2 activation in HeLa cells; the classical MAPK cascade exerts negative feedback control over the MKK5/ERK5 pathway; ERK5 is not a significant activator of MAPK-activated protein kinase-1/RSK in HeLa cells (negative finding).\",\n      \"method\": \"Phospho-specific antibodies, pharmacological inhibitors (U0126, PD184352) at different concentrations\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous phosphorylation measured with specific antibodies, multiple inhibitor concentrations, single lab\",\n      \"pmids\": [\"11478941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"BMK1 activation protects endothelial cells from apoptosis; constitutively active MEK5 activates BMK1 and inhibits caspase-3 activity and apoptosis; BMK1 phosphorylates Bad on Ser112 and Ser136 independently of Akt, PKA, or p90RSK; dominant-negative BMK1 stimulates apoptosis and reduces Bad phosphorylation.\",\n      \"method\": \"Overexpression of CA-MEK5 and DN-BMK1, MTT assay, caspase-3 assay, phospho-Bad immunoblot, kinase assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary gain- and loss-of-function experiments with defined molecular readouts, replicated across conditions\",\n      \"pmids\": [\"14670836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"WNK1 activates ERK5 through MEKK2 and MEKK3; WNK1 phosphorylates both MEKK2 and MEKK3 in vitro and activates MEKK3 in cells; MEKK2/MEKK3 co-immunoprecipitate with endogenous WNK1; ERK5 activation by EGF is attenuated by WNK1 siRNA knockdown, placing WNK1 upstream of MEKK2/3 in the ERK5 pathway.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, dominant-negative expression, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP plus in vitro kinase assay plus dominant-negative plus siRNA, multiple orthogonal methods\",\n      \"pmids\": [\"14681216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MEK5beta (short splice variant) inhibits EGF-induced BMK1 activation and MEK5alpha-induced MEF2 transcriptional activity; MEK5beta co-immunoprecipitates with BMK1 and competitively prevents MEK5alpha-BMK1 association, explaining its dominant-negative behavior.\",\n      \"method\": \"Co-immunoprecipitation, kinase assay, reporter assay, overexpression of splice variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus kinase and reporter assays, mechanism defined, single lab\",\n      \"pmids\": [\"14583600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Conditional genetic ablation of BMK1 in adult mice leads to lethality with vascular leakage, endothelial cell rounding, misalignment, and apoptosis; endothelial-specific BMK1 KO recapitulates cardiovascular defects; in vitro BMK1 removal causes endothelial death partially via deregulation of the direct substrate MEF2C. Cardiomyocyte-specific BMK1 KO mice develop normally.\",\n      \"method\": \"Conditional knockout mice (Mx1-Cre), histology, in vitro siRNA/knockdown, MEF2C reporter assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with tissue-specific phenotyping and in vitro mechanistic follow-up identifying MEF2C as direct substrate\",\n      \"pmids\": [\"15085193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BMK1/ERK5 negatively regulates HIF1α by promoting its ubiquitination and proteasomal degradation; constitutively active MEK5 reduces HIF1α protein levels and inhibits HIF1α-driven angiogenesis and EC migration; dominant-negative BMK1 enhances HIF1α activity.\",\n      \"method\": \"Reporter assay, immunoblot, ubiquitination inhibitors, overexpression of CA-MEK5 and DN-BMK1, Matrigel angiogenesis assay, EC migration assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with gain/loss of function, single lab\",\n      \"pmids\": [\"15879308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ERK5 binds to and phosphorylates p90 RSK in vitro, causing RSK activation; the common docking (CD) domain of ERK5 and the D domain of RSK mediate their association; the large C-terminal domain of ERK5 is not required for RSK binding or activation; activation of ERK5 weakens its binding to RSK suggesting RSK is released upon ERK5 activation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, domain deletion analysis\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus Co-IP plus domain mapping, single lab\",\n      \"pmids\": [\"16626623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERK5 controls EGF-induced Slug expression and keratinocyte migration; Erk5 pathway inhibition blocks keratinocyte migration and alters desmosome organization; shRNA knockdown of Erk5 reduces motility and Slug induction in response to EGF.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibition, wound healing assay, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with defined phenotypic and molecular readouts, single lab\",\n      \"pmids\": [\"18716062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In endothelial cells, MEK5-BMK1 (but not MEK1-ERK1/2) signaling mediates flow-induced inhibition of TNF-α-activated JNK; selective MEK5 inhibitor BIX02188 completely reverses the flow-mediated inhibition of JNK activation.\",\n      \"method\": \"Pharmacological inhibitors (PD184352 at selective concentrations, BIX02188), kinase assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective pharmacological dissection with two inhibitors, single lab\",\n      \"pmids\": [\"18358237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERK5/BMK1 is required for optimal CSF-1-induced macrophage proliferation; ERK5 activation by CSF-1 is Src family kinase-dependent; following CSF-1 stimulation, active ERK5 translocates from cytosol to nucleus; ERK5 siRNA reduces c-Jun phosphorylation/expression and increases p27 expression.\",\n      \"method\": \"siRNA knockdown, kinase assay, nuclear fractionation, immunoblot, DNA synthesis assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined molecular phenotype and subcellular localization, single lab\",\n      \"pmids\": [\"18322228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Constitutive MEK5/ERK5 activation strongly inhibits endothelial cell migration, increases focal contact number and actin stress fibers, reduces p130Cas expression (a key mediator of directed migration), and decreases focal contact turnover.\",\n      \"method\": \"Retroviral gene transfer (CA-MEK5), cell migration assay, immunofluorescence, immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined molecular and cellular phenotype, single lab\",\n      \"pmids\": [\"19605361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ERK1/2, but not ERK5, is necessary and sufficient for c-Fos phosphorylation and transcriptional activation; c-Fos expression is normal in ERK5−/− cells; however, ERK5−/− cells are defective for c-Jun expression, which is rescued by ERK5 re-expression.\",\n      \"method\": \"Conditional kinase activation, selective MEK inhibitors, ERK5-null fibroblasts, reporter assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout cells plus selective pharmacological inhibitors plus conditional kinases, multiple orthogonal approaches\",\n      \"pmids\": [\"19249353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDK1 co-precipitates with ERK5 in mitotic cells and its activity is required for ERK5 phosphorylation at multiple C-terminal sites during mitosis (a second MEK5-independent phosphorylation pathway); mitotic C-terminal phosphorylation controls ERK5 nuclear-cytoplasmic shuttling and transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, CDK1 inhibitor (RO3306), phosphorylation site mapping, subcellular fractionation, reporter assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus pharmacological inhibition plus localization analysis, single lab\",\n      \"pmids\": [\"20736311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BMK1 interacts with PML isoform IV and phosphorylates PML, inhibiting its tumor-suppressor function and PML-dependent p21 activation; the BMK1 inhibitor XMD8-92 blocks tumor cell proliferation in vitro and inhibits tumor growth in vivo by ~95%.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, cell proliferation assay, xenograft mouse model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP plus in vitro kinase assay plus in vivo xenograft with pharmacological inhibitor, multiple orthogonal methods\",\n      \"pmids\": [\"20832753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Activated BMK1 preferentially associates with PML isoform IV and disrupts PML-MDM2 interaction, suppressing p53 activation; BMK1 deactivation combined with doxorubicin synergistically enhances MDM2 nucleolar sequestration and PML-mediated p53 upregulation.\",\n      \"method\": \"Co-immunoprecipitation, immunoblot, reporter assay, in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional signaling readouts, single lab\",\n      \"pmids\": [\"22869143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BMK1 signaling suppresses EMT: BMK1 elevation augments E-cadherin-mediated cell-cell adhesion and reduces mesenchymal markers, while BMK1 silencing promotes Snail nuclear accumulation via Akt/GSK3β signaling activated through DEPTOR-mediated mTOR inhibition.\",\n      \"method\": \"siRNA knockdown, overexpression, immunoblot, cell adhesion/motility assay, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with molecular pathway delineation, single lab\",\n      \"pmids\": [\"22282661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"X-ray crystal structure of ERK5 (MAPK7) kinase domain in complex with a benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one inhibitor was determined; specific residue differences in the ATP-binding site distinguish ERK5 from ERK1/2, p38, and JNKs, providing a structural basis for inhibitor selectivity.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determination, foundational structural data for ERK5 kinase domain\",\n      \"pmids\": [\"23656407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERK5 is degraded via the ubiquitin-proteasome system in a process mediated by the tumor suppressor VHL through a prolyl hydroxylation-dependent mechanism; ERK5 knockdown in pVHL-negative cell lines decreases proliferation and migration.\",\n      \"method\": \"Transient transfection, siRNA knockdown, immunoblot, proteasome inhibitors\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — VHL-dependent degradation established with proteasome inhibitors and functional cell assays, single lab\",\n      \"pmids\": [\"23730213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ALK activates ERK5 through a PI3K-AKT-MEKK3-MEK5 pathway; ALK-induced MYCN transcription and neuroblastoma cell proliferation require ERK5; pharmacological or siRNA inhibition of ERK5 suppresses neuroblastoma cell proliferation and enhances the anti-tumor efficacy of the ALK inhibitor crizotinib.\",\n      \"method\": \"Pharmacological inhibitors, siRNA knockdown, reporter assay, xenograft models\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway delineation using multiple inhibitors plus siRNA plus in vivo xenograft validation\",\n      \"pmids\": [\"25351247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ERK5 activation in macrophages promotes efferocytosis; macrophage-specific ERK5-null mice show reduced efferocytosis and accelerated atherosclerotic plaque formation on a hypercholesterolemic background.\",\n      \"method\": \"Conditional macrophage-specific ERK5 knockout mice, efferocytosis assays, atherosclerosis model\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic KO with defined functional phenotype and in vivo disease model\",\n      \"pmids\": [\"25001623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ERK5 activation inhibits endothelial cell migration via a KLF2-dependent downregulation of PAK1 mRNA and protein; KLF2 (but not KLF4) knockdown prevents ERK5-mediated PAK1 repression and restores migration capacity.\",\n      \"method\": \"Constitutively active MEK5 expression, siRNA knockdown (KLF2, KLF4, PAK1), qRT-PCR, immunoblot, migration assay\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with specific siRNA rescue, single lab\",\n      \"pmids\": [\"25388666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pak2 (but not Pak1) signals through the Bmk1/Erk5 pathway to regulate endothelial development and function; endothelial Pak2 depletion causes embryonic lethality and adult vascular permeability; these defects are mediated through the Bmk1/Erk5 pathway.\",\n      \"method\": \"Conditional knockout mice, epistasis experiments, in vitro kinase assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis using conditional KO mice with functional phenotypic readouts, single lab\",\n      \"pmids\": [\"26391956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Phosphorylation of ERK5 at Thr732 by ERK1/2 (downstream of oncogenic Ras or growth factors) promotes ERK5 nuclear localization and MEF2C transcriptional activity, independently of TEY motif phosphorylation; ERK5-T732A mutant remains cytosolic under basal conditions.\",\n      \"method\": \"Site-directed mutagenesis (T732A, T732E), pharmacological inhibitors, subcellular fractionation, reporter assay, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus localization studies plus reporter assays in single lab\",\n      \"pmids\": [\"25689862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ERK5 kinase inhibitors paradoxically activate ERK5 transcriptional activity through its C-terminal TAD domain; inhibitor binding to the kinase domain promotes conformational changes that drive nuclear translocation and gene transcription; kinase-active drug-resistant ERK5 mutants confirmed that direct inhibitor binding to the kinase domain is required for paradoxical transcriptional activation.\",\n      \"method\": \"Drug-resistant kinase mutants, nuclear localization assay, reporter assay, kinase inhibitor panel\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — drug-resistant mutant approach plus multiple functional assays, mechanistically rigorous, published in Nature Communications\",\n      \"pmids\": [\"32170057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Selective ERK5 kinase inhibitors (lacking bromodomain activity) have no antiinflammatory or antiproliferative activity, while previously reported ERK5 inhibitors derive their efficacy from off-target bromodomain inhibition; ERK5 genetic deletion/depletion phenotypes likely arise from non-catalytic (kinase-independent) functions of ERK5.\",\n      \"method\": \"Selective inhibitor synthesis and characterization, KINOMEscan, bromodomain binding assays, cell proliferation 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 — rigorous selectivity profiling with orthogonal assays demonstrating off-target activity of prior inhibitors\",\n      \"pmids\": [\"27679845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of Erk1/2 in intestinal epithelial cells results in supraphysiological ERK5 pathway activity; targeting both ERK1/2 and ERK5 more effectively suppresses cell proliferation than targeting either alone in intestinal organoids and CRC lines, demonstrating ERK5 as a bypass route for proliferation upon ERK1/2 abrogation.\",\n      \"method\": \"Conditional Erk1/2 knockout mice, intestinal organoids, siRNA, pharmacological inhibitors\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus pharmacological epistasis plus organoid models, multiple orthogonal approaches\",\n      \"pmids\": [\"27187615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YAP promotes myogenic differentiation via the MEK5-ERK5 pathway through a Src/c-Abl/MEKK3 cascade; YAP physically interacts with MEKK3 (via PPGY motif at aa 178-181) and ERK5 as shown by co-immunoprecipitation; MEKK3 Y181F mutation inhibits MEK5/ERK5 activation and myogenic differentiation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, pharmacological inhibitors, Western blot, differentiation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis plus functional differentiation assays, single lab\",\n      \"pmids\": [\"28356344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Oncogenic BRAF positively regulates ERK5 expression, phosphorylation, and nuclear localization; both ERK5 kinase and transcriptional transactivation activities are enhanced by BRAF; combined inhibition of MEK5 and BRAFV600E is required to decrease nuclear ERK5, which is critical for cell proliferation.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibitors, immunofluorescence (nuclear ERK5), colony formation assay, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological dissection with subcellular localization readout and in vivo validation, single lab\",\n      \"pmids\": [\"29483645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERK5 SUMOylation at Lys6/Lys22 is required for nuclear translocation and cancer cell proliferation; MEK5 activation or Cdc37 overexpression induces SUMO-2 modification of ERK5; SUMO site mutation (K6R/K22R) abolishes nuclear ERK5 localization; SENP2 overexpression abolishes endogenous ERK5 nuclear localization in response to EGF.\",\n      \"method\": \"SUMO site mutagenesis, immunofluorescence, immunoblot, cell proliferation assay, SENP2 overexpression\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus localization plus functional proliferation assays, single lab\",\n      \"pmids\": [\"32209980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Shear stress activates PIEZO1, causing calcium influx that activates CaMKII, which interacts with and activates MEKK3 to promote MEKK3/MEK5/ERK5 signaling and ultimately KLF2/4 transcription; endothelial-specific Piezo1 deletion reduces KLF2/4 expression in vivo.\",\n      \"method\": \"Conditional endothelial Piezo1 KO mice, co-immunoprecipitation (CaMKII-MEKK3), pharmacological inhibitors, shear stress assays, qRT-PCR\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO plus Co-IP plus pathway inhibition, single lab\",\n      \"pmids\": [\"35883633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERK5 S496 phosphorylation mediates senescence-associated secretory phenotype (SASP) and senescence-associated stemness in macrophages by upregulating AHR; ERK5 S496 phosphorylation induces NRF2 SUMOylation at K518, inhibiting NRF2 transcriptional activity without altering ERK5 catalytic activity; S496A knock-in mice are protected from atherosclerosis.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse (S496A), RNA sequencing, imaging mass cytometry, SUMOylation assay, metabolic flux analysis, pharmacological ERK5 inhibitors\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — knock-in mouse model plus multiple orthogonal biochemical assays identifying specific phosphorylation site mechanism\",\n      \"pmids\": [\"37264926\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAPK7/ERK5/BMK1 is a dual-function protein containing an N-terminal kinase domain (activated by MEK5 via dual TEY phosphorylation, with upstream inputs from MEKK2/3 and WNK1) and a unique C-terminal domain harboring transcriptional activation, nuclear localization, and MEF2-interaction modules; activated ERK5 translocates to the nucleus (regulated by C-terminal autophosphorylation, CDK1-mediated mitotic phosphorylation, SUMOylation at K6/K22, and ERK1/2-mediated Thr732 phosphorylation) where it directly phosphorylates and coactivates MEF2 transcription factors, phosphorylates Sap1a, and engages NF-κB signaling, while in the cytoplasm it phosphorylates substrates including SGK (Ser78), Bad (Ser112/136), PML, and p90 RSK to promote cell survival, proliferation, and suppress apoptosis and EMT; paradoxically, ERK5 kinase inhibitors can activate ERK5 transcriptional activity through conformational changes in the kinase domain, and many reported phenotypes attributed to ERK5 kinase activity may reflect non-catalytic functions of the protein.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAPK7 (ERK5/BMK1) is a dual-function MAP kinase that couples growth-factor, mechanical, and oxidative-stress signaling to transcriptional programs governing cell proliferation, survival, and vascular/endothelial homeostasis [#0, #3, #18]. It carries an N-terminal kinase domain bearing a TEY dual-phosphorylation motif and a distinctive large C-terminal region that contains a transcriptional activation domain, a nuclear localization signal, and a MEF2-interaction module, the latter required for ERK5 to bind, phosphorylate, and coactivate MEF2 transcription factors [#0, #2, #8, #10]. Activation flows through a dedicated module in which MEKK2 or MEKK3 (cell-type-specifically) feed into MEK5, which dually phosphorylates ERK5, with WNK1 acting upstream of the MEKKs and diverse inputs (EGF/NGF receptor tyrosine kinases, RET-Y1062, ALK via PI3K-AKT, oncogenic BRAF, fluid shear stress via PIEZO1/CaMKII, and H2O2 via c-Src) converging on this cascade [#3, #5, #7, #13, #16, #32, #41, #43]. Nuclear translocation and transcriptional output are gated by multiple post-translational events distinct from TEY phosphorylation: C-terminal autophosphorylation, CDK1-mediated mitotic phosphorylation, SUMOylation at Lys6/Lys22, and ERK1/2-mediated Thr732 phosphorylation [#10, #26, #36, #42]. In addition to MEF2 and the Ets factor Sap1a, ERK5 phosphorylates SGK (Ser78), Bad (Ser112/136), PML, and p90 RSK, and engages NF-\\u03baB, promoting proliferation and survival while inhibiting apoptosis [#4, #9, #11, #15, #20, #27]. Genetic ablation establishes ERK5 as essential for endothelial integrity, where its loss causes vascular leakage, endothelial apoptosis, and lethality partly through deregulation of MEF2C [#18], and it drives macrophage efferocytosis, EMT suppression, and tumor proliferation [#27, #29, #33]. A critical reinterpretation of this biology comes from work showing that ERK5 kinase inhibitors paradoxically activate its C-terminal transcriptional activity through kinase-domain conformational changes, that several reported ERK5 inhibitors act through off-target bromodomain inhibition, and that many genetic-loss phenotypes likely reflect non-catalytic functions of the protein [#37, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that ERK5/BMK1 was a genuinely distinct MAP kinase rather than an ERK1/2 paralog set the stage for asking what unique signals it transduces.\",\n      \"evidence\": \"Molecular cloning and sequence analysis of an 816-residue kinase with a TEY motif but a divergent C-terminus and loop-12\",\n      \"pmids\": [\"7646528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No upstream activator or substrate identified\", \"Function of the unique C-terminal domain unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identifying selective activation by H2O2, distinct from ERK1/2 stimuli, provided the first physiological context (oxidative/vascular stress) for ERK5 signaling.\",\n      \"evidence\": \"Kinase activity assays with multiple stimuli and calcium chelation in vascular smooth muscle cells\",\n      \"pmids\": [\"8663194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream kinase cascade not defined\", \"Downstream effectors unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linking ERK5 to MEF2 and to EGF-driven proliferation defined its two core outputs: direct transcription-factor coactivation and cell-cycle entry.\",\n      \"evidence\": \"Y2H, GST pulldown, Co-IP, in vitro kinase and reporter assays (MEF2); dominant-negative BMK1 with cell-cycle/BrdU analysis (EGF proliferation)\",\n      \"pmids\": [\"9753748\", \"9790194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activating kinases for MEK5 not yet identified\", \"Mechanism of nuclear targeting unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining the MEKK3-MEK5-ERK5 cascade and a second substrate (Sap1a) built the canonical three-tier module and broadened its transcriptional reach to SRE/c-Fos.\",\n      \"evidence\": \"Y2H and reciprocal Co-IP for MEKK3-MEK5; dominant-negative genetics, in vitro kinase and reporter assays for Sap1a; mechanistic dissection of shear-stress activation\",\n      \"pmids\": [\"10593883\", \"10473620\", \"9867822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specificity of MEKK usage not yet appreciated\", \"Upstream input to MEKK3 undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping the C-terminal TAD, NLS, MEF2-interaction and oligomerization modules, plus an alternative MEKK2 input and an NF-\\u03baB/RSK link, established the molecular architecture underlying ERK5's dual kinase/transcriptional nature.\",\n      \"evidence\": \"Systematic domain deletion/mutagenesis with kinase, reporter and localization readouts; Y2H/Co-IP for MEKK2; reporter and focus-formation assays for NF-\\u03baB\",\n      \"pmids\": [\"11046135\", \"11139578\", \"11073940\", \"11118448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling nuclear translocation only partly defined\", \"Direct NF-\\u03baB substrate not identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying SGK (Ser78) and Bad-adjacent survival signaling, plus RET-Y1062 and redox/c-Src inputs, connected ERK5 to growth-factor proliferation and cell-survival programs through specific phospho-substrates and additional receptor inputs.\",\n      \"evidence\": \"Y2H, Co-IP, in vitro kinase assays with site mapping (SGK); mutagenesis and kinase/reporter assays (RET); inhibitor and dominant-negative dissection (c-Src/MEF2C); negative-feedback mapping by ERK1/2\",\n      \"pmids\": [\"11254654\", \"11237712\", \"11782488\", \"11478941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of each substrate not established\", \"Hierarchy among multiple receptor inputs unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing ERK5 phosphorylates Bad at Ser112/136 independently of Akt/PKA/RSK and protects endothelial cells from apoptosis defined a direct anti-apoptotic mechanism.\",\n      \"evidence\": \"CA-MEK5 and DN-BMK1 overexpression, caspase-3 and MTT assays, phospho-Bad immunoblot, kinase assay\",\n      \"pmids\": [\"14670836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect Bad phosphorylation in vivo not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placing WNK1 upstream of MEKK2/3 and defining the dominant-negative MEK5beta splice variant clarified pathway regulation at the input and adaptor levels.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, dominant-negative and siRNA (WNK1); Co-IP and competition assays (MEK5beta)\",\n      \"pmids\": [\"14681216\", \"14583600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological stimuli engaging WNK1-ERK5 not defined\", \"Tissue distribution of MEK5beta unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Conditional knockout established ERK5 as essential in vivo for endothelial integrity and vascular survival, acting partly through MEF2C, anchoring the pathway in cardiovascular biology.\",\n      \"evidence\": \"Mx1-Cre and endothelial-specific knockout mice with histology; in vitro knockdown and MEF2C reporter assay\",\n      \"pmids\": [\"15085193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic vs non-catalytic contribution to phenotype not dissected\", \"Full set of essential transcriptional targets unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying ERK5-driven HIF1alpha degradation and a direct p90 RSK interaction extended ERK5 control to angiogenic and downstream-kinase signaling.\",\n      \"evidence\": \"Reporter, immunoblot, ubiquitination and angiogenesis/migration assays (HIF1alpha); Co-IP, in vitro kinase and domain mapping (RSK)\",\n      \"pmids\": [\"15879308\", \"16626623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ERK5 promotes HIF1alpha ubiquitination unclear\", \"RSK activation by ERK5 contradicts prior negative finding in HeLa\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Roles in keratinocyte migration/Slug, macrophage proliferation with nuclear translocation, and flow-mediated JNK suppression broadened ERK5's cellular repertoire beyond endothelium.\",\n      \"evidence\": \"shRNA and wound healing (keratinocytes); siRNA, fractionation and DNA synthesis (macrophages); selective MEK5 inhibitor BIX02188 (JNK suppression)\",\n      \"pmids\": [\"18716062\", \"18322228\", \"18358237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in each context not defined\", \"Catalytic dependence not tested with selective tools\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic dissection separated ERK1/2 (c-Fos) from ERK5 (c-Jun) outputs and revealed ERK5-controlled inhibition of endothelial migration via p130Cas, refining the non-redundant transcriptional functions of ERK5.\",\n      \"evidence\": \"ERK5-null fibroblasts, selective MEK inhibitors and conditional kinases (c-Fos/c-Jun); CA-MEK5 retroviral transfer and migration/immunofluorescence (p130Cas)\",\n      \"pmids\": [\"19249353\", \"19605361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of c-Jun control by ERK5 not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovering CDK1-mediated mitotic phosphorylation and the PML interaction established a MEK5-independent regulatory route and a tumor-relevant substrate, with XMD8-92 validating ERK5 as an anti-cancer target.\",\n      \"evidence\": \"Co-IP, CDK1 inhibitor, phospho-site mapping and fractionation (mitotic); Co-IP, in vitro kinase, proliferation and xenograft assays (PML/XMD8-92)\",\n      \"pmids\": [\"20736311\", \"20832753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"XMD8-92 specificity later questioned\", \"Functional consequence of mitotic phosphorylation incompletely defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking ERK5-PML to p53 suppression and defining ERK5 suppression of EMT positioned the kinase as both tumor-promoting (via PML/p53) and metastasis-restraining (via E-cadherin/Snail).\",\n      \"evidence\": \"Co-IP, reporter and tumor models (PML-MDM2-p53); siRNA/overexpression with adhesion, motility and metastasis assays (EMT)\",\n      \"pmids\": [\"22869143\", \"22282661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context determining pro- vs anti-tumor role unclear\", \"Direct PML phosphosites linking to p53 axis not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Solving the kinase-domain crystal structure and defining VHL-mediated degradation provided structural and stability-control foundations for the pathway.\",\n      \"evidence\": \"X-ray crystallography of the kinase domain with a selective inhibitor; transfection, siRNA, proteasome inhibitors (VHL degradation)\",\n      \"pmids\": [\"23656407\", \"23730213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the regulatory C-terminal domain\", \"Prolyl-hydroxylation/VHL recognition motif on ERK5 not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ALK-PI3K-MEKK3-MEK5-ERK5 driving MYCN in neuroblastoma, KLF2-dependent migration control, and a macrophage efferocytosis/atherosclerosis role expanded ERK5 into oncology and cardiovascular disease as a therapeutic node.\",\n      \"evidence\": \"Inhibitors, siRNA, reporter and xenograft (ALK/MYCN); CA-MEK5 with KLF2/PAK1 knockdown (migration); macrophage-specific KO with efferocytosis and atherosclerosis models\",\n      \"pmids\": [\"25351247\", \"25388666\", \"25001623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic dependence of these phenotypes not tested with clean tools\", \"How ERK5 selects MYCN/KLF2 programs unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapping Thr732 phosphorylation by ERK1/2 and Pak2-dependent endothelial signaling defined additional activation/localization inputs feeding ERK5 nuclear function and vascular development.\",\n      \"evidence\": \"T732A/T732E mutagenesis, fractionation, reporter and immunofluorescence (Thr732); conditional KO and epistasis (Pak2)\",\n      \"pmids\": [\"25689862\", \"26391956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of Thr732 vs TEY phosphorylation in vivo unclear\", \"Mechanism linking Pak2 to the cascade incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The discovery that kinase inhibitors paradoxically activate ERK5 transcription, that prior inhibitors acted via off-target bromodomain inhibition, and that ERK1/2 loss unmasks ERK5 as a proliferation bypass forced a major reinterpretation: many ERK5 phenotypes reflect non-catalytic functions or tool artifacts.\",\n      \"evidence\": \"Drug-resistant kinase mutants with localization/reporter assays; selective inhibitor synthesis with KINOMEscan and bromodomain profiling; Erk1/2 conditional KO with organoids and CRC lines\",\n      \"pmids\": [\"32170057\", \"27679845\", \"27187615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which catalytic substrates retain physiological relevance unresolved\", \"Mechanism of paradoxical TAD activation by inhibitors not fully structural\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining YAP-MEKK3-MEK5-ERK5 in myogenic differentiation extended the pathway into developmental/mechanotransduction biology with a physical YAP-MEKK3 interaction.\",\n      \"evidence\": \"Co-IP, PPGY-motif and MEKK3 Y181F mutagenesis, inhibitors, differentiation assays\",\n      \"pmids\": [\"28356344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ERK5 transcriptional targets in myogenesis not defined\", \"Catalytic dependence not isolated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing oncogenic BRAF enhances both ERK5 expression and nuclear localization, requiring combined MEK5/BRAF inhibition, reinforced ERK5 as a co-targetable node in RAF-driven cancers.\",\n      \"evidence\": \"siRNA, inhibitors, nuclear-ERK5 immunofluorescence, colony formation and xenograft\",\n      \"pmids\": [\"29483645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which BRAF drives ERK5 nuclear localization unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing SUMOylation at Lys6/Lys22 as required for nuclear translocation and proliferation added a defined PTM controlling ERK5's transcriptional access.\",\n      \"evidence\": \"SUMO-site mutagenesis (K6R/K22R), immunofluorescence, immunoblot, SENP2 overexpression, proliferation assays\",\n      \"pmids\": [\"32209980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO E3 ligase for ERK5 not identified\", \"Interplay with other nuclear-targeting PTMs unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining the PIEZO1-calcium-CaMKII-MEKK3 input clarified how mechanical shear stress is transduced to ERK5-driven KLF2/4 transcription in endothelium.\",\n      \"evidence\": \"Endothelial Piezo1 KO mice, CaMKII-MEKK3 Co-IP, inhibitors, shear-stress assays, qRT-PCR\",\n      \"pmids\": [\"35883633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CaMKII phosphosite on MEKK3 not mapped\", \"Catalytic vs scaffold role of ERK5 in KLF2/4 induction unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying ERK5 S496 phosphorylation as driving SASP/senescence via NRF2 SUMOylation without altering catalytic activity provided direct in vivo proof of a kinase-independent, atheroprotective-relevant ERK5 function.\",\n      \"evidence\": \"S496A CRISPR knock-in mice, RNA-seq, imaging mass cytometry, SUMOylation and metabolic-flux assays, ERK5 inhibitors\",\n      \"pmids\": [\"37264926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for S496 phosphorylation not defined\", \"Generality of non-catalytic mechanism across other phenotypes unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which ERK5 phenotypes depend on its catalytic kinase activity versus non-catalytic/scaffold and transcriptional functions, and the structure-function basis of its regulatory C-terminal domain is undefined.\",\n      \"evidence\": \"No direct experimental resolution in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Catalytic vs non-catalytic contributions not systematically separated for most substrates\", \"No structure of the C-terminal TAD/NLS/MEF2-interaction region\", \"Physiological substrate set under selective, on-target inhibition unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 11, 15, 20, 27]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 11, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 10, 37]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 23, 26, 36, 42]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 23, 36]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 7, 16, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 4, 8, 25]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [27, 32, 33, 41]}\n    ],\n    \"complexes\": [\"MEKK2/3-MEK5-ERK5 module\"],\n    \"partners\": [\"MEK5\", \"MEKK2\", \"MEKK3\", \"MEF2C\", \"WNK1\", \"RPS6KA1\", \"PML\", \"SGK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}