{"gene":"MAP3K7","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2016,"finding":"Gain-of-function mutations in MAP3K7 (including the recurrent p.Pro485Leu near the coiled-coil domain and three kinase-domain missense mutations) cause frontometaphyseal dysplasia type 2. The recurrent mutation does not destabilize TAK1 or impair homodimerization or TAB2 binding, but increases TAK1 autophosphorylation and alters activity of multiple signaling pathways downstream of the TAK1 complex.","method":"Whole-exome sequencing, Sanger sequencing, autophosphorylation assays, homodimerization assays, TAB2 binding assays, downstream pathway activity assays in patient-derived cells","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical assays (autophosphorylation, dimerization, binding, pathway activity) in a single rigorous study with 19 affected individuals and functional validation","pmids":["27426733"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function heterozygous MAP3K7 mutations cause cardiospondylocarpofacial syndrome by impairing MAPK-p38 signaling; expression of non-canonical TGF-β-driven target genes was impaired in fibroblasts from affected individuals, supporting loss of transcriptional control of the TGF-β–MAPK–p38 pathway.","method":"Whole-exome sequencing, reporter gene assays for MAPK-p38 signaling in patient fibroblasts","journal":"American Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblast functional assays with pathway readout, single lab, two complementary methods","pmids":["27426734"],"is_preprint":false},{"year":2020,"finding":"The CSCF-associated MAP3K7 splice variant c.737-7A>G generates an in-frame insertion of 2 amino acids (p.Asn245_Gly246insValVal) in the kinase activation loop, which impairs TAK1 autophosphorylation, disrupts physical binding to TAB1 (shown by co-immunoprecipitation), impairs TGF-β-mediated α-SMA cytoskeleton assembly and cell migration, and causes defective autophagy in patient fibroblasts.","method":"RNA splice analysis, computational protein dynamics modeling, co-immunoprecipitation, autophosphorylation assays, α-SMA cytoskeleton and migration assays, autophagy assays in patient fibroblasts","journal":"Biochimica et Biophysica Acta. Molecular Basis of Disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods including Co-IP, kinase activity assay, and cellular functional assays in patient-derived material","pmids":["32105826"],"is_preprint":false},{"year":2021,"finding":"TRIM31, an E3 ubiquitin ligase, interacts with MAP3K7 and catalyzes K48-linked polyubiquitination at lysine 72 of MAP3K7, leading to its proteasomal degradation and consequent negative regulation of TGF-β1-mediated Smad and MAPK/NF-κB signaling pathways in hypertensive renal disease.","method":"Co-immunoprecipitation, ubiquitination assays with K48-linkage specificity, site-directed mutagenesis (K72), proteasome inhibitor experiments, TRIM31 KO and AAV-overexpression mouse models, Western blotting for downstream pathway components","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution of ubiquitination with site identification, reciprocal Co-IP, in vivo genetic KO and OE models, multiple orthogonal methods","pmids":["34584221"],"is_preprint":false},{"year":2022,"finding":"SF3B1 mutations cause aberrant splicing of MAP3K7, generating a transcript with a premature termination codon targeted by nonsense-mediated decay, thereby reducing MAP3K7 protein. MAP3K7 is an upstream positive effector of p38 MAPK; its loss deactivates p38 MAPK, leading to premature down-regulation of GATA1, accelerated erythroid differentiation, erythroid hyperplasia, and apoptosis, explaining the anemia in SF3B1-mutated MDS.","method":"Isogenic SF3B1 WT vs. mutant cell lines, normal human CD34+ cells, MDS patient cells; splice analysis, cycloheximide NMD assay, MAP3K7 knockdown/rescue, p38 MAPK activity assays, GATA1 expression analysis, erythroid differentiation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (splicing, NMD, kinase pathway, differentiation readouts) in isogenic lines and patient cells, mechanistic pathway established end-to-end","pmids":["34930825"],"is_preprint":false},{"year":2021,"finding":"MAP3K7 aberrant splicing induced by SF3B1 K700E mutation uses an aberrant 3′ splice site and alternative branchpoint sequence, and requires both a normal and an alternative upstream polypyrimidine tract; the aberrantly spliced transcript contains a premature termination codon targeted by NMD.","method":"SF3B1 K700E transfection in HEK293T cells, cycloheximide NMD assay, splice site and branchpoint mutational analysis","journal":"Journal of Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based splice reporter with mutagenesis, single lab, multiple sequence elements tested","pmids":["33751071"],"is_preprint":false},{"year":2021,"finding":"MAP3K7 activates IKKβ in response to TNFα, which phosphorylates AR protein, targeting it for TRCP1/2 E3 ligase-mediated polyubiquitination and proteasomal degradation; Map3k7 knockout in mouse prostate increased AR protein levels and activity, and AR protein levels were inversely correlated with MAP3K7 in patient specimens.","method":"Map3k7 conditional knockout mouse model, TNFα stimulation, AR ubiquitination assays, IKKβ phosphorylation assays, patient specimen correlation, prostate cancer cell lines","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo genetic KO model, biochemical ubiquitination assay, mechanistic pathway defined through IKKβ and TRCP1/2, validated in patient specimens","pmids":["34158377"],"is_preprint":false},{"year":2021,"finding":"iRhom2 binds MAP3K7 and facilitates MAP3K7 phosphorylation in response to high-fat diet, activating the NF-κB cascade and promoting c-Jun N-terminal kinase/IRS1 signaling while disturbing AKT/GSK3β-associated insulin signaling; iRhom2/MAP3K7 axis is required for iRhom2-regulated liver steatosis.","method":"Co-immunoprecipitation of iRhom2 and MAP3K7, iRhom2 KO and OE mouse models (including myeloid-specific), bone marrow transplantation, phosphorylation assays, downstream pathway readouts","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple genetic in vivo models (KO, OE, bone marrow transplant), and downstream pathway mechanistic validation","pmids":["32592194"],"is_preprint":false},{"year":2012,"finding":"TAK1 (MAP3K7) activation requires TAB1- or TAB2-dependent mechanisms; Tab1/Tab2 double deletion phenocopied Tak1 single deletion in hematopoietic stem cells, abolishing HSC reconstitution activity. TAK1 signaling maintains HSCs via two mechanisms: preventing TNF-dependent cell death (Tnfr1 deficiency partially rescued Tak1-deficient HSC reconstitution) and a TNF-independent long-term HSC maintenance pathway.","method":"Competitive transplantation assays, Tak1/Tab1/Tab2 conditional knockout mouse models, Tnfr1 double-knockout epistasis, LSK cell proliferation and death assays","journal":"PloS ONE","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple conditional KO models and competitive transplantation, two distinct mechanisms demonstrated","pmids":["23226465"],"is_preprint":false},{"year":2013,"finding":"In NK cells, a Fyn–ADAP complex exclusively regulates inflammatory cytokine production (not cytotoxicity) through a Carma1–Bcl-10–MAP3K7 signaling axis downstream of PI(3)K and PLC-γ2.","method":"Genetic knockouts/knockdowns of pathway components in NK cells, NK cell cytotoxicity assays, cytokine production assays, epistasis analysis","journal":"Nature Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis across multiple pathway nodes with dual functional readouts (cytotoxicity vs. cytokine production), published in high-quality journal","pmids":["24036998"],"is_preprint":false},{"year":2016,"finding":"TAK1 (MAP3K7) is required for BMP-induced adipocyte differentiation; TAK1 promotes PPARγ transcriptional activity synergistically with TAB1, and TAK1 ablation specifically in adipocytes reduced high-fat diet-induced weight gain and improved glucose tolerance.","method":"TAK1 inhibitor treatment, siRNA knockdown in C3H10T1/2 MSCs and 3T3-L1 preadipocytes, adipocyte-specific conditional knockout mice, PPARγ transactivation assay, co-activation assay with TAB1","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO in vivo plus in vitro siRNA and transactivation assays, single lab","pmids":["27293199"],"is_preprint":false},{"year":2018,"finding":"Genetic inactivation of Map3k7 in FOXD1-expressing mesangial/interstitial cells causes spontaneous postnatal kidney scarring; MAP3K7 loss skews MAPK signaling in mesangial cells (depressed p38, elevated JNK), and elevated JNK negatively regulates PDGFRβ expression, leading to loss of mesangial PDGFRβ.","method":"Foxd1-Cre conditional Map3k7 knockout mice, p38 and JNK phosphorylation assays, PDGFRβ expression analysis, isolated mesangial cell studies with JNK inhibition","journal":"American Journal of Physiology. Renal Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with mechanistic follow-up in isolated cells, single lab","pmids":["29667914"],"is_preprint":false},{"year":2019,"finding":"MAP3K7 promotes HCC cell proliferation, migration, and invasion through the MAP3K7–mTOR axis; MAP3K7 knockdown reduced mTOR phosphorylation and expression in HCC cells, and MAP3K7 expression was positively correlated with mTOR in patient tumors.","method":"Kinome siRNA library screen, pharmacological inhibition, stable MAP3K7 knockdown, spheroid culture, xenograft mouse model, mTOR phosphorylation Western blot, primary HCC cells","journal":"Frontiers in Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinome screen followed by genetic and pharmacological validation with in vivo xenograft, single lab","pmids":["31214512"],"is_preprint":false},{"year":2019,"finding":"Loss of MAP3K7 in prostate cancer cells disrupts homologous recombination repair by reducing expression of ATM, ATR, BRCA2, RAD51, blocking BRCA1 phosphorylation, reducing RAD51 foci, and increasing γH2AX foci, sensitizing cells to CDK1/2 inhibition and DNA-damaging agents.","method":"MAP3K7/CHD1 knockdown in mouse and human prostate cells, CDK1/2 inhibitor (dinaciclib) treatment, HR gene expression analysis, RAD51 and γH2AX immunofluorescence foci assays, BRCA1 phosphorylation Western blot, PARP inhibitor co-treatment cytotoxicity","journal":"Molecular Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays establishing HR pathway disruption, single lab","pmids":["31300540"],"is_preprint":false},{"year":2015,"finding":"In multikinase inhibitor-induced hand-foot skin reaction, sorafenib enters keratinocytes via the OAT6 transporter (SLC22A20) and then inhibits MAP3K7 (TAK1) kinase activity, inducing keratinocyte cell death; in situ kinome profiling identified MAP3K7 as the intracellular sorafenib target.","method":"Transporter-directed RNAi screen in keratinocytes, in situ kinome profiling, MAP3K7 functional assays, in vivo keratinocyte injury model with OAT6 inhibitor rescue","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi screen plus kinome profiling plus in vivo rescue, single lab","pmids":["26677977"],"is_preprint":false},{"year":2016,"finding":"MAP3K7 (TAK1) acts as the key signaling hub for bacterial killing, chemokine production, and monocyte-to-macrophage differentiation; kinomics and phosphoproteomics revealed that MAP3K7 is central to rewiring of MAPK signaling networks during differentiation.","method":"Kinomics and phosphoproteomics of THP-1 cells before/after macrophage differentiation, MAP3K7 functional inhibition with phenotypic readouts (bacterial killing, chemokine production, differentiation)","journal":"Frontiers in Cell and Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics plus functional assays, single lab","pmids":["27066479"],"is_preprint":false},{"year":2012,"finding":"Activin A stimulates murine and ovine Fshb transcription via SMAD proteins (SMAD3 and SMAD4), but NOT through TAK1 (MAP3K7) or p38 MAPK; Map3k7 siRNA failed to antagonize activin A-stimulated Fshb promoter activity, and activin A did not stimulate p38 phosphorylation in LβT2 gonadotrope-like cells.","method":"Map3k7 siRNA knockdown, TAK1 inhibitor (5Z-7-Oxozeaenol) dose-response, constitutively active ALK4 reporter assay, p38 phosphorylation Western blot, Smad3/Smad4 siRNA knockdown, luciferase promoter assays","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal negative results with positive controls establishing SMAD dependence, single lab — negative finding explicitly reported","pmids":["22549017"],"is_preprint":false},{"year":2017,"finding":"Overexpression of constitutively active MAP3K7 in mouse ES-derived cardiomyocytes directs differentiation toward the sinoatrial node (SAN) lineage, producing cells with SAN markers, morphologies, and electrophysiological behaviors; Map3k7 is upregulated in the sinus venosus, the source of SAN progenitors.","method":"Transgenic ES cell overexpression of Map3k7, embryoid body differentiation, electrophysiology, molecular marker analysis","journal":"PloS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in ES-derived cells with electrophysiological and molecular validation, single lab","pmids":["29281682"],"is_preprint":false},{"year":2019,"finding":"Map3k7 is required for endoderm differentiation; its overexpression in ES cells increases cardiogenic endoderm formation and visceral endoderm markers, enhancing cardiac differentiation of co-cultured wild-type cells. Downstream targets activated by Map3k7 include p38 MAPK, JNK, and NLK; inhibition of Map3k7 phosphorylation blocked these targets and impaired endoderm differentiation.","method":"Map3k7-overexpressing ES cell lines, chimeric embryoid bodies with MHCα::GFP reporter, 5Z-7-oxozeaenol inhibitor treatment, Western blot for JNK/p38/NLK, qRT-PCR for lineage markers","journal":"Journal of Molecular and Cellular Cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric EB rescue experiment plus inhibitor studies with pathway readouts, single lab","pmids":["31668971"],"is_preprint":false},{"year":2024,"finding":"MAP3K7 Val50Ala variant (CSCF-causing) significantly reduces TAK1 autophosphorylation levels in HEK293T cells; the Val50 residue is critical for ATP binding and its substitution disrupts kinase domain structure. The variant differentially affects downstream signaling (p38, p65/NF-κB, JNK) compared to FMD2-causing variants; TGF-β stimulation partially restores altered phosphorylation.","method":"In vitro overexpression in HEK293T cells, Western blotting for TAK1 phosphorylation and downstream targets, protein 3D modeling, sequence conservation analysis, TGF-β stimulation rescue experiment","journal":"Human Mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based kinase activity assays with multiple downstream readouts and TGF-β rescue, single lab","pmids":["42040894"],"is_preprint":false},{"year":2025,"finding":"TAK1 (MAP3K7) acts as a cancer-intrinsic cytoprotective checkpoint by integrating TNF and IFNγ signals; TAK1 deficiency redirects combined TNF/IFNγ signaling to promote inflammatory cell death via RIPK1 and Caspase-8, amplifies IFNγ pathway output, and leads to proteasomal degradation of cFLIP, enhancing Complex II formation. TAK1 inhibition or loss attenuates tumor growth in immune-competent mice.","method":"Kinome-wide CRISPR/Cas9 sgRNA screen, TAK1 knockout and inhibition, TNF/IFNγ cytokine stimulation assays, RIPK1/Caspase-8 pathway analysis, cFLIP degradation assays, Complex II formation assays, syngeneic mouse tumor models, adoptive cell therapy","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen followed by mechanistic in vitro and in vivo validation, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.05.09.652721"],"is_preprint":true},{"year":2025,"finding":"TAK1 (MAP3K7) phosphorylates EphA2 at Serine 897, which in turn phosphorylates RAD51 at Tyrosine 315; TAK1 inhibition induces DNA damage and cytoplasmic DNA leakage activating cGAS–STING, thereby promoting adaptive immune cell infiltration in pancreatic cancer.","method":"Proteomics, in vitro kinase/phosphorylation assays, TAK1 inhibitor (Takinib), MAP3K7 conditional genetic deletion in autochthonous GEMM (p48-Cre;TP53flox/flox;LSL-KRASG12D), scRNA-seq, flow cytometry, mIHC, cGAS-STING pathway assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — proteomics plus phosphorylation assays plus in vivo GEMM model, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.08.681226"],"is_preprint":true},{"year":2021,"finding":"MAP3K7 loss drives increased androgen receptor (AR) target gene expression and increased AR-v7 expression in prostate cancer; CHD1 loss mainly expands the AR cistrome, while MAP3K7 loss primarily increases AR target gene transcription. Co-suppression of MAP3K7 and CHD1 confers resistance to enzalutamide.","method":"Engineered prostate cancer cell lines with MAP3K7/CHD1 co-suppression, AR ChIP-seq/cistrome analysis, AR target gene expression profiling, enzalutamide resistance assays, clinical cohort AR-v7 expression","journal":"Molecular Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered cell lines with cistrome and gene expression analyses plus drug resistance readout, single lab","pmids":["33846123"],"is_preprint":false},{"year":2026,"finding":"Loss of MAP3K7 (and CHD1) potentiates the transcriptional response to IFN-γ in cancer cells, sensitizing them to tumor-reactive T cell killing; MAP3K7/CHD1 co-loss increases susceptibility to immune checkpoint blockade in syngeneic mouse models, associated with elevated intra-tumoral CD8+ T cell numbers and activation.","method":"Whole-genome CRISPR-Cas9 KO screens in tumoroid-T cell co-cultures and isogenic IFN-signaling-deficient models, syngeneic mouse melanoma model with Chd1/Map3k7 deficiency, flow cytometry for T cell infiltration and activation","journal":"Cell Reports Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen validated in in vivo syngeneic model, single study","pmids":["41564866"],"is_preprint":false},{"year":2024,"finding":"MAP3K7 phosphorylation is increased in both muscle hypertrophy (Texel sheep) and cancer-induced cachexia; in C2C12 cells, blockade of TAK1 phosphorylation reduces downstream phosphorylation of p38, JNK, and HSP27, and acutely promotes muscle fiber hypertrophy, but continuous blockade leads to muscle fiber failure.","method":"Multiplex kinase array of ES cells with/without TAK1 stimulation, phosphoprotein analysis in Texel sheep and cachexia mouse models, C2C12 myofiber differentiation with TAK1 phosphorylation blockade","journal":"Biology Open","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — kinase array plus multi-model comparison, but no direct target identification or mutagenesis, single lab","pmids":["39211992"],"is_preprint":false}],"current_model":"MAP3K7 (TAK1) is a serine/threonine kinase that serves as a central signaling hub downstream of TGF-β, TNF, IL-1, BMP, and Wnt, operating in a complex with TAB1/TAB2 to autophosphorylate and activate downstream MAPK (p38, JNK) and NF-κB (via IKKβ) pathways; its activity is regulated by ubiquitination (K48-linked degradation via TRIM31), by binding partners (TAB1 synergizes for PPARγ transactivation; iRhom2 promotes its phosphorylation), and by missplicing (SF3B1 mutations cause NMD of MAP3K7 mRNA, depleting the kinase and collapsing p38-GATA1 signaling in erythropoiesis); gain-of-function mutations increase autophosphorylation causing skeletal dysplasia (FMD2), while loss-of-function mutations impair TGF-β–p38 signaling causing cardiospondylocarpofacial syndrome; in cancer, MAP3K7 mediates AR protein degradation via IKKβ–TRCP1/2, phosphorylates EphA2 to maintain genomic integrity via RAD51, and acts as an intrinsic cytoprotective checkpoint by integrating TNF/IFNγ to suppress inflammatory cell death through cFLIP stabilization and Complex II inhibition."},"narrative":{"mechanistic_narrative":"MAP3K7 (TAK1) is a serine/threonine kinase that operates as a central signaling hub, transducing TGF-β, BMP, TNF, and cytokine inputs to activate downstream MAPK (p38, JNK, NLK) and NF-κB pathways through TAB1- and TAB2-dependent mechanisms [PMID:23226465, PMID:31668971]. Its catalytic activation depends on autophosphorylation gated by an intact kinase domain and physical engagement of TAB1, with the activation-loop and ATP-binding residues being critical: disease variants that insert residues into the activation loop or substitute Val50 disrupt TAB1 binding and autophosphorylation, while gain-of-function mutations near the coiled-coil and kinase domains increase autophosphorylation [PMID:27426733, PMID:32105826, PMID:42040894]. Kinase output is set by ubiquitin-dependent turnover — the E3 ligase TRIM31 catalyzes K48-linked polyubiquitination at Lys72 to drive proteasomal degradation and dampen TGF-β1–Smad/MAPK/NF-κB signaling — and by transcript availability, since SF3B1-mutant mis-splicing introduces a premature termination codon that triggers nonsense-mediated decay and depletes the kinase [PMID:34584221, PMID:34930825, PMID:33751071]. Through these pathways MAP3K7 governs lineage-specific differentiation programs, including BMP-driven adipogenesis via synergy with TAB1 on PPARγ, erythroid maturation via a p38–GATA1 axis, and cardiac/endodermal specification [PMID:27293199, PMID:34930825, PMID:29281682, PMID:31668971]. Bidirectional dysregulation produces distinct skeletal disorders: gain-of-function mutations cause frontometaphyseal dysplasia type 2, whereas loss-of-function mutations cause cardiospondylocarpofacial syndrome by impairing TGF-β–p38 signaling [PMID:27426733, PMID:27426734, PMID:32105826]. In cancer, MAP3K7 controls androgen receptor protein levels through an IKKβ–βTRCP degradation route and acts as a cytoprotective checkpoint that restrains TNF/IFNγ-driven inflammatory cell death [PMID:34158377, PMID:bio_10.1101_2025.05.09.652721].","teleology":[{"year":2012,"claim":"Established that TAK1 activation in vivo requires TAB1/TAB2 adaptors and that TAK1 sustains hematopoietic stem cells both by blocking TNF-dependent death and through a TNF-independent maintenance route, defining the adaptor dependence and physiological output of the kinase.","evidence":"Conditional knockout of Tak1/Tab1/Tab2 with Tnfr1 epistasis and competitive transplantation in mice","pmids":["23226465"],"confidence":"High","gaps":["Does not resolve the molecular nature of the TNF-independent maintenance pathway","Adaptor stoichiometry and direct activation mechanism not biochemically reconstituted"]},{"year":2012,"claim":"Delineated pathway specificity by showing activin A drives Fshb transcription through SMAD3/SMAD4 and NOT through TAK1 or p38, ruling out TAK1 in this gonadotrope context.","evidence":"Map3k7 siRNA, TAK1 inhibitor, and p38 phosphorylation negative controls in LβT2 cells","pmids":["22549017"],"confidence":"Medium","gaps":["Negative result confined to a single cell type and promoter","Does not exclude TAK1 contribution to other activin-responsive genes"]},{"year":2013,"claim":"Positioned MAP3K7 within a Carma1–Bcl-10 immune signaling axis that selectively controls NK-cell cytokine production rather than cytotoxicity, distinguishing its functional outputs in immune effectors.","evidence":"Genetic epistasis across pathway nodes with dual cytotoxicity/cytokine readouts in NK cells","pmids":["24036998"],"confidence":"High","gaps":["Direct substrates of MAP3K7 in this axis not identified","Mechanism segregating cytokine from cytotoxic output unresolved"]},{"year":2016,"claim":"Resolved that bidirectional MAP3K7 mutations cause opposite skeletal phenotypes — gain-of-function (increased autophosphorylation) drives frontometaphyseal dysplasia type 2 while loss-of-function impairs TGF-β–p38 signaling causing cardiospondylocarpofacial syndrome — linking kinase dosage to human disease.","evidence":"Whole-exome sequencing with autophosphorylation, dimerization, binding, and pathway assays in patient cells","pmids":["27426733","27426734"],"confidence":"High","gaps":["How a single recurrent mutation alters multiple downstream pathways without affecting dimerization or TAB2 binding is unexplained","Tissue selectivity of skeletal phenotypes not addressed"]},{"year":2016,"claim":"Defined MAP3K7 as a required effector of BMP-induced adipogenesis acting via PPARγ transactivation with TAB1, connecting the kinase to metabolic differentiation and diet-induced obesity.","evidence":"Inhibitor/siRNA in preadipocytes, adipocyte-specific conditional KO mice, PPARγ transactivation and TAB1 co-activation assays","pmids":["27293199"],"confidence":"Medium","gaps":["Whether TAK1 phosphorylates PPARγ directly or acts through co-activators is unclear","Single-lab finding"]},{"year":2016,"claim":"Identified MAP3K7 as the kinome hub rewiring MAPK networks during monocyte-to-macrophage differentiation and as the intracellular target of sorafenib, explaining keratinocyte toxicity in hand-foot skin reaction.","evidence":"Phosphoproteomics in THP-1 cells; transporter RNAi screen with in situ kinome profiling and in vivo rescue","pmids":["27066479","26677977"],"confidence":"Medium","gaps":["Direct substrate map during differentiation not defined","On-target vs off-target contributions of sorafenib not fully separated"]},{"year":2017,"claim":"Demonstrated that constitutively active MAP3K7 directs cardiomyocyte differentiation toward the sinoatrial node lineage, implicating the kinase in cardiac conduction-cell specification.","evidence":"Transgenic ES-cell overexpression with electrophysiology and marker analysis","pmids":["29281682"],"confidence":"Medium","gaps":["Downstream transcriptional effectors of SAN specification not identified","Requires loss-of-function confirmation"]},{"year":2018,"claim":"Showed MAP3K7 maintains renal mesangial homeostasis by balancing p38 and JNK output, where its loss elevates JNK and suppresses PDGFRβ, causing spontaneous kidney scarring.","evidence":"Foxd1-Cre conditional Map3k7 KO mice with p38/JNK and PDGFRβ readouts and JNK inhibition in isolated cells","pmids":["29667914"],"confidence":"Medium","gaps":["Mechanism linking JNK to PDGFRβ repression not defined","Single-lab in vivo model"]},{"year":2019,"claim":"Expanded MAP3K7 roles into endoderm differentiation and HCC progression, activating p38/JNK/NLK to drive cardiogenic endoderm and engaging an mTOR axis to promote tumor growth.","evidence":"ES-cell overexpression with chimeric embryoid bodies and inhibitor studies; kinome siRNA screen with knockdown and xenografts in HCC","pmids":["31668971","31214512"],"confidence":"Medium","gaps":["Whether MAP3K7 acts directly upstream of mTOR or indirectly is unresolved","NLK activation mechanism not characterized"]},{"year":2021,"claim":"Established multiple layers of MAP3K7 regulation and output: TRIM31-mediated K48 ubiquitination at Lys72 controls its degradation, iRhom2 binding promotes its phosphorylation in metabolic disease, and TAK1–IKKβ controls androgen receptor protein stability and HR-repair gene expression in prostate cancer.","evidence":"Reconstituted ubiquitination with site mutagenesis and KO/OE mouse models; reciprocal Co-IP and genetic models; conditional KO mice with AR ubiquitination and HR foci assays","pmids":["34584221","32592194","34158377","31300540","33846123"],"confidence":"High","gaps":["How these distinct regulatory inputs are integrated on one kinase is unknown","Direct substrate phosphorylation events for AR and HR-gene control not fully mapped"]},{"year":2022,"claim":"Connected SF3B1-mutant mis-splicing to MAP3K7 depletion via NMD, defining an end-to-end mechanism whereby kinase loss deactivates p38, downregulates GATA1, and disrupts erythropoiesis in MDS.","evidence":"Splice/branchpoint analysis and NMD assays in isogenic and patient cells with knockdown/rescue and erythroid differentiation readouts","pmids":["34930825","33751071"],"confidence":"High","gaps":["Why MAP3K7 is selectively vulnerable to SF3B1-driven mis-splicing is unclear","Direct GATA1 regulatory mechanism downstream of p38 not detailed"]},{"year":2024,"claim":"Refined the structural basis of CSCF pathogenicity by showing the Val50Ala variant disrupts ATP binding and kinase-domain structure to reduce autophosphorylation, with TGF-β partially restoring downstream signaling, distinguishing it from FMD2 variants.","evidence":"HEK293T overexpression with phosphorylation Western blots, 3D modeling, and TGF-β rescue","pmids":["42040894"],"confidence":"Medium","gaps":["Endogenous patient-cell validation not performed","Mechanism of differential downstream pathway effects vs FMD2 unresolved"]},{"year":2025,"claim":"Proposed MAP3K7 as a cancer-intrinsic cytoprotective checkpoint and a regulator of genomic integrity: it integrates TNF/IFNγ to suppress RIPK1/Caspase-8 inflammatory death by stabilizing cFLIP, and phosphorylates EphA2-Ser897 to control RAD51 and prevent cGAS-STING activation.","evidence":"Kinome CRISPR screen, KO/inhibition, and syngeneic tumor models (preprint); proteomics, kinase assays, and GEMM (preprint)","pmids":["bio_10.1101_2025.05.09.652721","bio_10.1101_2025.10.08.681226"],"confidence":"Medium","gaps":["Findings reside in preprints not yet peer-reviewed","Direct EphA2 and cFLIP phosphorylation/degradation steps require independent confirmation"]},{"year":2026,"claim":"Linked MAP3K7 loss to enhanced anti-tumor immunity, showing co-loss with CHD1 potentiates IFN-γ responses and sensitizes tumors to T-cell killing and checkpoint blockade.","evidence":"Genome-wide CRISPR screens in tumoroid–T cell co-cultures and syngeneic melanoma model","pmids":["41564866"],"confidence":"Medium","gaps":["Mechanism by which MAP3K7 normally restrains IFN-γ transcriptional output not fully defined","Contribution of MAP3K7 loss independent of CHD1 not isolated"]},{"year":null,"claim":"It remains unresolved how MAP3K7 integrates its many regulatory inputs (TAB adaptors, TRIM31 ubiquitination, iRhom2, transcript splicing) to select among its divergent downstream outputs across distinct tissues and disease contexts.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of context-dependent substrate selection","Direct phosphorylation targets in most contexts remain unmapped","Structural basis of differential signaling between disease variants undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,6,19,21]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,6,21]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[19]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,8,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,15,20,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,17,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[20]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,5]}],"complexes":["TAK1-TAB1-TAB2 complex"],"partners":["TAB1","TAB2","TRIM31","IRHOM2","IKBKB","EPHA2","CARMA1","BCL10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43318","full_name":"Mitogen-activated protein kinase kinase kinase 7","aliases":["Transforming growth factor-beta-activated kinase 1","TGF-beta-activated kinase 1"],"length_aa":606,"mass_kda":67.2,"function":"Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway (PubMed:10094049, PubMed:11460167, PubMed:12589052, PubMed:16845370, PubMed:16893890, PubMed:21512573, PubMed:8663074, PubMed:9079627). Plays an important role in the cascades of cellular responses evoked by changes in the environment (PubMed:10094049, PubMed:11460167, PubMed:12589052, PubMed:16845370, PubMed:16893890, PubMed:21512573, PubMed:8663074, PubMed:9079627). Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR) (PubMed:16893890, PubMed:9079627). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7 (PubMed:11460167, PubMed:8663074). These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs); both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1) (PubMed:11460167, PubMed:12589052, PubMed:8663074). Independently of MAP2Ks and p38 MAPKs, acts as a key activator of NF-kappa-B by promoting activation of the I-kappa-B-kinase (IKK) core complex (PubMed:12589052, PubMed:8663074). Mechanistically, recruited to polyubiquitin chains of RIPK2 and IKBKG/NEMO via TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3, and catalyzes phosphorylation and activation of IKBKB/IKKB component of the IKK complex, leading to NF-kappa-B activation (PubMed:10094049, PubMed:11460167). In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B (PubMed:16893890). Promotes TRIM5 capsid-specific restriction activity (PubMed:21512573). Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (By similarity). Phosphorylates STING1 in response to cGAMP-activation, promoting association between STEEP1 and STING1 and STING1 translocation to COPII vesicles (PubMed:37832545)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/O43318/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP3K7","classification":"Not Classified","n_dependent_lines":125,"n_total_lines":1208,"dependency_fraction":0.10347682119205298},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000135341","cell_line_id":"CID001199","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"TAB1","stoichiometry":10.0},{"gene":"TAB2","stoichiometry":10.0},{"gene":"TAB3","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001199","total_profiled":1310},"omim":[{"mim_id":"620373","title":"ADIPOSE-SECRETED SIGNALING PROTEIN; ADISSP","url":"https://www.omim.org/entry/620373"},{"mim_id":"620293","title":"TMEM9 DOMAIN FAMILY, MEMBER B; TMEM9B","url":"https://www.omim.org/entry/620293"},{"mim_id":"617137","title":"FRONTOMETAPHYSEAL DYSPLASIA 2; FMD2","url":"https://www.omim.org/entry/617137"},{"mim_id":"616786","title":"MITOGEN-ACTIVATED PROTEIN KINASE-BINDING PROTEIN 1; MAPKBP1","url":"https://www.omim.org/entry/616786"},{"mim_id":"614798","title":"PELLINO E3 UBIQUITIN PROTEIN LIGASE 2; PELI2","url":"https://www.omim.org/entry/614798"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAP3K7"},"hgnc":{"alias_symbol":["MEKK7"],"prev_symbol":["TAK1"]},"alphafold":{"accession":"O43318","domains":[{"cath_id":"3.30.200.20","chopping":"26-106","consensus_level":"medium","plddt":89.9135,"start":26,"end":106},{"cath_id":"1.10.510.10","chopping":"107-299","consensus_level":"medium","plddt":90.2931,"start":107,"end":299},{"cath_id":"1.20.5","chopping":"513-606","consensus_level":"medium","plddt":85.9677,"start":513,"end":606}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43318","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43318-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43318-F1-predicted_aligned_error_v6.png","plddt_mean":69.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP3K7","jax_strain_url":"https://www.jax.org/strain/search?query=MAP3K7"},"sequence":{"accession":"O43318","fasta_url":"https://rest.uniprot.org/uniprotkb/O43318.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43318/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43318"}},"corpus_meta":[{"pmid":"23370768","id":"PMC_23370768","title":"Genomic 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The recurrent mutation does not destabilize TAK1 or impair homodimerization or TAB2 binding, but increases TAK1 autophosphorylation and alters activity of multiple signaling pathways downstream of the TAK1 complex.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, autophosphorylation assays, homodimerization assays, TAB2 binding assays, downstream pathway activity assays in patient-derived cells\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical assays (autophosphorylation, dimerization, binding, pathway activity) in a single rigorous study with 19 affected individuals and functional validation\",\n      \"pmids\": [\"27426733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function heterozygous MAP3K7 mutations cause cardiospondylocarpofacial syndrome by impairing MAPK-p38 signaling; expression of non-canonical TGF-β-driven target genes was impaired in fibroblasts from affected individuals, supporting loss of transcriptional control of the TGF-β–MAPK–p38 pathway.\",\n      \"method\": \"Whole-exome sequencing, reporter gene assays for MAPK-p38 signaling in patient fibroblasts\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblast functional assays with pathway readout, single lab, two complementary methods\",\n      \"pmids\": [\"27426734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CSCF-associated MAP3K7 splice variant c.737-7A>G generates an in-frame insertion of 2 amino acids (p.Asn245_Gly246insValVal) in the kinase activation loop, which impairs TAK1 autophosphorylation, disrupts physical binding to TAB1 (shown by co-immunoprecipitation), impairs TGF-β-mediated α-SMA cytoskeleton assembly and cell migration, and causes defective autophagy in patient fibroblasts.\",\n      \"method\": \"RNA splice analysis, computational protein dynamics modeling, co-immunoprecipitation, autophosphorylation assays, α-SMA cytoskeleton and migration assays, autophagy assays in patient fibroblasts\",\n      \"journal\": \"Biochimica et Biophysica Acta. Molecular Basis of Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods including Co-IP, kinase activity assay, and cellular functional assays in patient-derived material\",\n      \"pmids\": [\"32105826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM31, an E3 ubiquitin ligase, interacts with MAP3K7 and catalyzes K48-linked polyubiquitination at lysine 72 of MAP3K7, leading to its proteasomal degradation and consequent negative regulation of TGF-β1-mediated Smad and MAPK/NF-κB signaling pathways in hypertensive renal disease.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with K48-linkage specificity, site-directed mutagenesis (K72), proteasome inhibitor experiments, TRIM31 KO and AAV-overexpression mouse models, Western blotting for downstream pathway components\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution of ubiquitination with site identification, reciprocal Co-IP, in vivo genetic KO and OE models, multiple orthogonal methods\",\n      \"pmids\": [\"34584221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SF3B1 mutations cause aberrant splicing of MAP3K7, generating a transcript with a premature termination codon targeted by nonsense-mediated decay, thereby reducing MAP3K7 protein. MAP3K7 is an upstream positive effector of p38 MAPK; its loss deactivates p38 MAPK, leading to premature down-regulation of GATA1, accelerated erythroid differentiation, erythroid hyperplasia, and apoptosis, explaining the anemia in SF3B1-mutated MDS.\",\n      \"method\": \"Isogenic SF3B1 WT vs. mutant cell lines, normal human CD34+ cells, MDS patient cells; splice analysis, cycloheximide NMD assay, MAP3K7 knockdown/rescue, p38 MAPK activity assays, GATA1 expression analysis, erythroid differentiation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (splicing, NMD, kinase pathway, differentiation readouts) in isogenic lines and patient cells, mechanistic pathway established end-to-end\",\n      \"pmids\": [\"34930825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAP3K7 aberrant splicing induced by SF3B1 K700E mutation uses an aberrant 3′ splice site and alternative branchpoint sequence, and requires both a normal and an alternative upstream polypyrimidine tract; the aberrantly spliced transcript contains a premature termination codon targeted by NMD.\",\n      \"method\": \"SF3B1 K700E transfection in HEK293T cells, cycloheximide NMD assay, splice site and branchpoint mutational analysis\",\n      \"journal\": \"Journal of Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based splice reporter with mutagenesis, single lab, multiple sequence elements tested\",\n      \"pmids\": [\"33751071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAP3K7 activates IKKβ in response to TNFα, which phosphorylates AR protein, targeting it for TRCP1/2 E3 ligase-mediated polyubiquitination and proteasomal degradation; Map3k7 knockout in mouse prostate increased AR protein levels and activity, and AR protein levels were inversely correlated with MAP3K7 in patient specimens.\",\n      \"method\": \"Map3k7 conditional knockout mouse model, TNFα stimulation, AR ubiquitination assays, IKKβ phosphorylation assays, patient specimen correlation, prostate cancer cell lines\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo genetic KO model, biochemical ubiquitination assay, mechanistic pathway defined through IKKβ and TRCP1/2, validated in patient specimens\",\n      \"pmids\": [\"34158377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"iRhom2 binds MAP3K7 and facilitates MAP3K7 phosphorylation in response to high-fat diet, activating the NF-κB cascade and promoting c-Jun N-terminal kinase/IRS1 signaling while disturbing AKT/GSK3β-associated insulin signaling; iRhom2/MAP3K7 axis is required for iRhom2-regulated liver steatosis.\",\n      \"method\": \"Co-immunoprecipitation of iRhom2 and MAP3K7, iRhom2 KO and OE mouse models (including myeloid-specific), bone marrow transplantation, phosphorylation assays, downstream pathway readouts\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple genetic in vivo models (KO, OE, bone marrow transplant), and downstream pathway mechanistic validation\",\n      \"pmids\": [\"32592194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TAK1 (MAP3K7) activation requires TAB1- or TAB2-dependent mechanisms; Tab1/Tab2 double deletion phenocopied Tak1 single deletion in hematopoietic stem cells, abolishing HSC reconstitution activity. TAK1 signaling maintains HSCs via two mechanisms: preventing TNF-dependent cell death (Tnfr1 deficiency partially rescued Tak1-deficient HSC reconstitution) and a TNF-independent long-term HSC maintenance pathway.\",\n      \"method\": \"Competitive transplantation assays, Tak1/Tab1/Tab2 conditional knockout mouse models, Tnfr1 double-knockout epistasis, LSK cell proliferation and death assays\",\n      \"journal\": \"PloS ONE\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple conditional KO models and competitive transplantation, two distinct mechanisms demonstrated\",\n      \"pmids\": [\"23226465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In NK cells, a Fyn–ADAP complex exclusively regulates inflammatory cytokine production (not cytotoxicity) through a Carma1–Bcl-10–MAP3K7 signaling axis downstream of PI(3)K and PLC-γ2.\",\n      \"method\": \"Genetic knockouts/knockdowns of pathway components in NK cells, NK cell cytotoxicity assays, cytokine production assays, epistasis analysis\",\n      \"journal\": \"Nature Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis across multiple pathway nodes with dual functional readouts (cytotoxicity vs. cytokine production), published in high-quality journal\",\n      \"pmids\": [\"24036998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TAK1 (MAP3K7) is required for BMP-induced adipocyte differentiation; TAK1 promotes PPARγ transcriptional activity synergistically with TAB1, and TAK1 ablation specifically in adipocytes reduced high-fat diet-induced weight gain and improved glucose tolerance.\",\n      \"method\": \"TAK1 inhibitor treatment, siRNA knockdown in C3H10T1/2 MSCs and 3T3-L1 preadipocytes, adipocyte-specific conditional knockout mice, PPARγ transactivation assay, co-activation assay with TAB1\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in vivo plus in vitro siRNA and transactivation assays, single lab\",\n      \"pmids\": [\"27293199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Genetic inactivation of Map3k7 in FOXD1-expressing mesangial/interstitial cells causes spontaneous postnatal kidney scarring; MAP3K7 loss skews MAPK signaling in mesangial cells (depressed p38, elevated JNK), and elevated JNK negatively regulates PDGFRβ expression, leading to loss of mesangial PDGFRβ.\",\n      \"method\": \"Foxd1-Cre conditional Map3k7 knockout mice, p38 and JNK phosphorylation assays, PDGFRβ expression analysis, isolated mesangial cell studies with JNK inhibition\",\n      \"journal\": \"American Journal of Physiology. Renal Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with mechanistic follow-up in isolated cells, single lab\",\n      \"pmids\": [\"29667914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAP3K7 promotes HCC cell proliferation, migration, and invasion through the MAP3K7–mTOR axis; MAP3K7 knockdown reduced mTOR phosphorylation and expression in HCC cells, and MAP3K7 expression was positively correlated with mTOR in patient tumors.\",\n      \"method\": \"Kinome siRNA library screen, pharmacological inhibition, stable MAP3K7 knockdown, spheroid culture, xenograft mouse model, mTOR phosphorylation Western blot, primary HCC cells\",\n      \"journal\": \"Frontiers in Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinome screen followed by genetic and pharmacological validation with in vivo xenograft, single lab\",\n      \"pmids\": [\"31214512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of MAP3K7 in prostate cancer cells disrupts homologous recombination repair by reducing expression of ATM, ATR, BRCA2, RAD51, blocking BRCA1 phosphorylation, reducing RAD51 foci, and increasing γH2AX foci, sensitizing cells to CDK1/2 inhibition and DNA-damaging agents.\",\n      \"method\": \"MAP3K7/CHD1 knockdown in mouse and human prostate cells, CDK1/2 inhibitor (dinaciclib) treatment, HR gene expression analysis, RAD51 and γH2AX immunofluorescence foci assays, BRCA1 phosphorylation Western blot, PARP inhibitor co-treatment cytotoxicity\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays establishing HR pathway disruption, single lab\",\n      \"pmids\": [\"31300540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In multikinase inhibitor-induced hand-foot skin reaction, sorafenib enters keratinocytes via the OAT6 transporter (SLC22A20) and then inhibits MAP3K7 (TAK1) kinase activity, inducing keratinocyte cell death; in situ kinome profiling identified MAP3K7 as the intracellular sorafenib target.\",\n      \"method\": \"Transporter-directed RNAi screen in keratinocytes, in situ kinome profiling, MAP3K7 functional assays, in vivo keratinocyte injury model with OAT6 inhibitor rescue\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi screen plus kinome profiling plus in vivo rescue, single lab\",\n      \"pmids\": [\"26677977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAP3K7 (TAK1) acts as the key signaling hub for bacterial killing, chemokine production, and monocyte-to-macrophage differentiation; kinomics and phosphoproteomics revealed that MAP3K7 is central to rewiring of MAPK signaling networks during differentiation.\",\n      \"method\": \"Kinomics and phosphoproteomics of THP-1 cells before/after macrophage differentiation, MAP3K7 functional inhibition with phenotypic readouts (bacterial killing, chemokine production, differentiation)\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics plus functional assays, single lab\",\n      \"pmids\": [\"27066479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Activin A stimulates murine and ovine Fshb transcription via SMAD proteins (SMAD3 and SMAD4), but NOT through TAK1 (MAP3K7) or p38 MAPK; Map3k7 siRNA failed to antagonize activin A-stimulated Fshb promoter activity, and activin A did not stimulate p38 phosphorylation in LβT2 gonadotrope-like cells.\",\n      \"method\": \"Map3k7 siRNA knockdown, TAK1 inhibitor (5Z-7-Oxozeaenol) dose-response, constitutively active ALK4 reporter assay, p38 phosphorylation Western blot, Smad3/Smad4 siRNA knockdown, luciferase promoter assays\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal negative results with positive controls establishing SMAD dependence, single lab — negative finding explicitly reported\",\n      \"pmids\": [\"22549017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of constitutively active MAP3K7 in mouse ES-derived cardiomyocytes directs differentiation toward the sinoatrial node (SAN) lineage, producing cells with SAN markers, morphologies, and electrophysiological behaviors; Map3k7 is upregulated in the sinus venosus, the source of SAN progenitors.\",\n      \"method\": \"Transgenic ES cell overexpression of Map3k7, embryoid body differentiation, electrophysiology, molecular marker analysis\",\n      \"journal\": \"PloS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in ES-derived cells with electrophysiological and molecular validation, single lab\",\n      \"pmids\": [\"29281682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Map3k7 is required for endoderm differentiation; its overexpression in ES cells increases cardiogenic endoderm formation and visceral endoderm markers, enhancing cardiac differentiation of co-cultured wild-type cells. Downstream targets activated by Map3k7 include p38 MAPK, JNK, and NLK; inhibition of Map3k7 phosphorylation blocked these targets and impaired endoderm differentiation.\",\n      \"method\": \"Map3k7-overexpressing ES cell lines, chimeric embryoid bodies with MHCα::GFP reporter, 5Z-7-oxozeaenol inhibitor treatment, Western blot for JNK/p38/NLK, qRT-PCR for lineage markers\",\n      \"journal\": \"Journal of Molecular and Cellular Cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric EB rescue experiment plus inhibitor studies with pathway readouts, single lab\",\n      \"pmids\": [\"31668971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAP3K7 Val50Ala variant (CSCF-causing) significantly reduces TAK1 autophosphorylation levels in HEK293T cells; the Val50 residue is critical for ATP binding and its substitution disrupts kinase domain structure. The variant differentially affects downstream signaling (p38, p65/NF-κB, JNK) compared to FMD2-causing variants; TGF-β stimulation partially restores altered phosphorylation.\",\n      \"method\": \"In vitro overexpression in HEK293T cells, Western blotting for TAK1 phosphorylation and downstream targets, protein 3D modeling, sequence conservation analysis, TGF-β stimulation rescue experiment\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based kinase activity assays with multiple downstream readouts and TGF-β rescue, single lab\",\n      \"pmids\": [\"42040894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAK1 (MAP3K7) acts as a cancer-intrinsic cytoprotective checkpoint by integrating TNF and IFNγ signals; TAK1 deficiency redirects combined TNF/IFNγ signaling to promote inflammatory cell death via RIPK1 and Caspase-8, amplifies IFNγ pathway output, and leads to proteasomal degradation of cFLIP, enhancing Complex II formation. TAK1 inhibition or loss attenuates tumor growth in immune-competent mice.\",\n      \"method\": \"Kinome-wide CRISPR/Cas9 sgRNA screen, TAK1 knockout and inhibition, TNF/IFNγ cytokine stimulation assays, RIPK1/Caspase-8 pathway analysis, cFLIP degradation assays, Complex II formation assays, syngeneic mouse tumor models, adoptive cell therapy\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen followed by mechanistic in vitro and in vivo validation, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.09.652721\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAK1 (MAP3K7) phosphorylates EphA2 at Serine 897, which in turn phosphorylates RAD51 at Tyrosine 315; TAK1 inhibition induces DNA damage and cytoplasmic DNA leakage activating cGAS–STING, thereby promoting adaptive immune cell infiltration in pancreatic cancer.\",\n      \"method\": \"Proteomics, in vitro kinase/phosphorylation assays, TAK1 inhibitor (Takinib), MAP3K7 conditional genetic deletion in autochthonous GEMM (p48-Cre;TP53flox/flox;LSL-KRASG12D), scRNA-seq, flow cytometry, mIHC, cGAS-STING pathway assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proteomics plus phosphorylation assays plus in vivo GEMM model, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.08.681226\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAP3K7 loss drives increased androgen receptor (AR) target gene expression and increased AR-v7 expression in prostate cancer; CHD1 loss mainly expands the AR cistrome, while MAP3K7 loss primarily increases AR target gene transcription. Co-suppression of MAP3K7 and CHD1 confers resistance to enzalutamide.\",\n      \"method\": \"Engineered prostate cancer cell lines with MAP3K7/CHD1 co-suppression, AR ChIP-seq/cistrome analysis, AR target gene expression profiling, enzalutamide resistance assays, clinical cohort AR-v7 expression\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered cell lines with cistrome and gene expression analyses plus drug resistance readout, single lab\",\n      \"pmids\": [\"33846123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of MAP3K7 (and CHD1) potentiates the transcriptional response to IFN-γ in cancer cells, sensitizing them to tumor-reactive T cell killing; MAP3K7/CHD1 co-loss increases susceptibility to immune checkpoint blockade in syngeneic mouse models, associated with elevated intra-tumoral CD8+ T cell numbers and activation.\",\n      \"method\": \"Whole-genome CRISPR-Cas9 KO screens in tumoroid-T cell co-cultures and isogenic IFN-signaling-deficient models, syngeneic mouse melanoma model with Chd1/Map3k7 deficiency, flow cytometry for T cell infiltration and activation\",\n      \"journal\": \"Cell Reports Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen validated in in vivo syngeneic model, single study\",\n      \"pmids\": [\"41564866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAP3K7 phosphorylation is increased in both muscle hypertrophy (Texel sheep) and cancer-induced cachexia; in C2C12 cells, blockade of TAK1 phosphorylation reduces downstream phosphorylation of p38, JNK, and HSP27, and acutely promotes muscle fiber hypertrophy, but continuous blockade leads to muscle fiber failure.\",\n      \"method\": \"Multiplex kinase array of ES cells with/without TAK1 stimulation, phosphoprotein analysis in Texel sheep and cachexia mouse models, C2C12 myofiber differentiation with TAK1 phosphorylation blockade\",\n      \"journal\": \"Biology Open\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — kinase array plus multi-model comparison, but no direct target identification or mutagenesis, single lab\",\n      \"pmids\": [\"39211992\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAP3K7 (TAK1) is a serine/threonine kinase that serves as a central signaling hub downstream of TGF-β, TNF, IL-1, BMP, and Wnt, operating in a complex with TAB1/TAB2 to autophosphorylate and activate downstream MAPK (p38, JNK) and NF-κB (via IKKβ) pathways; its activity is regulated by ubiquitination (K48-linked degradation via TRIM31), by binding partners (TAB1 synergizes for PPARγ transactivation; iRhom2 promotes its phosphorylation), and by missplicing (SF3B1 mutations cause NMD of MAP3K7 mRNA, depleting the kinase and collapsing p38-GATA1 signaling in erythropoiesis); gain-of-function mutations increase autophosphorylation causing skeletal dysplasia (FMD2), while loss-of-function mutations impair TGF-β–p38 signaling causing cardiospondylocarpofacial syndrome; in cancer, MAP3K7 mediates AR protein degradation via IKKβ–TRCP1/2, phosphorylates EphA2 to maintain genomic integrity via RAD51, and acts as an intrinsic cytoprotective checkpoint by integrating TNF/IFNγ to suppress inflammatory cell death through cFLIP stabilization and Complex II inhibition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAP3K7 (TAK1) is a serine/threonine kinase that operates as a central signaling hub, transducing TGF-\\u03b2, BMP, TNF, and cytokine inputs to activate downstream MAPK (p38, JNK, NLK) and NF-\\u03baB pathways through TAB1- and TAB2-dependent mechanisms [#8, #18]. Its catalytic activation depends on autophosphorylation gated by an intact kinase domain and physical engagement of TAB1, with the activation-loop and ATP-binding residues being critical: disease variants that insert residues into the activation loop or substitute Val50 disrupt TAB1 binding and autophosphorylation, while gain-of-function mutations near the coiled-coil and kinase domains increase autophosphorylation [#0, #2, #19]. Kinase output is set by ubiquitin-dependent turnover \\u2014 the E3 ligase TRIM31 catalyzes K48-linked polyubiquitination at Lys72 to drive proteasomal degradation and dampen TGF-\\u03b21\\u2013Smad/MAPK/NF-\\u03baB signaling \\u2014 and by transcript availability, since SF3B1-mutant mis-splicing introduces a premature termination codon that triggers nonsense-mediated decay and depletes the kinase [#3, #4, #5]. Through these pathways MAP3K7 governs lineage-specific differentiation programs, including BMP-driven adipogenesis via synergy with TAB1 on PPAR\\u03b3, erythroid maturation via a p38\\u2013GATA1 axis, and cardiac/endodermal specification [#10, #4, #17, #18]. Bidirectional dysregulation produces distinct skeletal disorders: gain-of-function mutations cause frontometaphyseal dysplasia type 2, whereas loss-of-function mutations cause cardiospondylocarpofacial syndrome by impairing TGF-\\u03b2\\u2013p38 signaling [#0, #1, #2]. In cancer, MAP3K7 controls androgen receptor protein levels through an IKK\\u03b2\\u2013\\u03b2TRCP degradation route and acts as a cytoprotective checkpoint that restrains TNF/IFN\\u03b3-driven inflammatory cell death [#6, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that TAK1 activation in vivo requires TAB1/TAB2 adaptors and that TAK1 sustains hematopoietic stem cells both by blocking TNF-dependent death and through a TNF-independent maintenance route, defining the adaptor dependence and physiological output of the kinase.\",\n      \"evidence\": \"Conditional knockout of Tak1/Tab1/Tab2 with Tnfr1 epistasis and competitive transplantation in mice\",\n      \"pmids\": [\"23226465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the molecular nature of the TNF-independent maintenance pathway\", \"Adaptor stoichiometry and direct activation mechanism not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Delineated pathway specificity by showing activin A drives Fshb transcription through SMAD3/SMAD4 and NOT through TAK1 or p38, ruling out TAK1 in this gonadotrope context.\",\n      \"evidence\": \"Map3k7 siRNA, TAK1 inhibitor, and p38 phosphorylation negative controls in L\\u03b2T2 cells\",\n      \"pmids\": [\"22549017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result confined to a single cell type and promoter\", \"Does not exclude TAK1 contribution to other activin-responsive genes\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Positioned MAP3K7 within a Carma1\\u2013Bcl-10 immune signaling axis that selectively controls NK-cell cytokine production rather than cytotoxicity, distinguishing its functional outputs in immune effectors.\",\n      \"evidence\": \"Genetic epistasis across pathway nodes with dual cytotoxicity/cytokine readouts in NK cells\",\n      \"pmids\": [\"24036998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates of MAP3K7 in this axis not identified\", \"Mechanism segregating cytokine from cytotoxic output unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved that bidirectional MAP3K7 mutations cause opposite skeletal phenotypes \\u2014 gain-of-function (increased autophosphorylation) drives frontometaphyseal dysplasia type 2 while loss-of-function impairs TGF-\\u03b2\\u2013p38 signaling causing cardiospondylocarpofacial syndrome \\u2014 linking kinase dosage to human disease.\",\n      \"evidence\": \"Whole-exome sequencing with autophosphorylation, dimerization, binding, and pathway assays in patient cells\",\n      \"pmids\": [\"27426733\", \"27426734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single recurrent mutation alters multiple downstream pathways without affecting dimerization or TAB2 binding is unexplained\", \"Tissue selectivity of skeletal phenotypes not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined MAP3K7 as a required effector of BMP-induced adipogenesis acting via PPAR\\u03b3 transactivation with TAB1, connecting the kinase to metabolic differentiation and diet-induced obesity.\",\n      \"evidence\": \"Inhibitor/siRNA in preadipocytes, adipocyte-specific conditional KO mice, PPAR\\u03b3 transactivation and TAB1 co-activation assays\",\n      \"pmids\": [\"27293199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TAK1 phosphorylates PPAR\\u03b3 directly or acts through co-activators is unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified MAP3K7 as the kinome hub rewiring MAPK networks during monocyte-to-macrophage differentiation and as the intracellular target of sorafenib, explaining keratinocyte toxicity in hand-foot skin reaction.\",\n      \"evidence\": \"Phosphoproteomics in THP-1 cells; transporter RNAi screen with in situ kinome profiling and in vivo rescue\",\n      \"pmids\": [\"27066479\", \"26677977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate map during differentiation not defined\", \"On-target vs off-target contributions of sorafenib not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that constitutively active MAP3K7 directs cardiomyocyte differentiation toward the sinoatrial node lineage, implicating the kinase in cardiac conduction-cell specification.\",\n      \"evidence\": \"Transgenic ES-cell overexpression with electrophysiology and marker analysis\",\n      \"pmids\": [\"29281682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream transcriptional effectors of SAN specification not identified\", \"Requires loss-of-function confirmation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed MAP3K7 maintains renal mesangial homeostasis by balancing p38 and JNK output, where its loss elevates JNK and suppresses PDGFR\\u03b2, causing spontaneous kidney scarring.\",\n      \"evidence\": \"Foxd1-Cre conditional Map3k7 KO mice with p38/JNK and PDGFR\\u03b2 readouts and JNK inhibition in isolated cells\",\n      \"pmids\": [\"29667914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking JNK to PDGFR\\u03b2 repression not defined\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded MAP3K7 roles into endoderm differentiation and HCC progression, activating p38/JNK/NLK to drive cardiogenic endoderm and engaging an mTOR axis to promote tumor growth.\",\n      \"evidence\": \"ES-cell overexpression with chimeric embryoid bodies and inhibitor studies; kinome siRNA screen with knockdown and xenografts in HCC\",\n      \"pmids\": [\"31668971\", \"31214512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAP3K7 acts directly upstream of mTOR or indirectly is unresolved\", \"NLK activation mechanism not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established multiple layers of MAP3K7 regulation and output: TRIM31-mediated K48 ubiquitination at Lys72 controls its degradation, iRhom2 binding promotes its phosphorylation in metabolic disease, and TAK1\\u2013IKK\\u03b2 controls androgen receptor protein stability and HR-repair gene expression in prostate cancer.\",\n      \"evidence\": \"Reconstituted ubiquitination with site mutagenesis and KO/OE mouse models; reciprocal Co-IP and genetic models; conditional KO mice with AR ubiquitination and HR foci assays\",\n      \"pmids\": [\"34584221\", \"32592194\", \"34158377\", \"31300540\", \"33846123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How these distinct regulatory inputs are integrated on one kinase is unknown\", \"Direct substrate phosphorylation events for AR and HR-gene control not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SF3B1-mutant mis-splicing to MAP3K7 depletion via NMD, defining an end-to-end mechanism whereby kinase loss deactivates p38, downregulates GATA1, and disrupts erythropoiesis in MDS.\",\n      \"evidence\": \"Splice/branchpoint analysis and NMD assays in isogenic and patient cells with knockdown/rescue and erythroid differentiation readouts\",\n      \"pmids\": [\"34930825\", \"33751071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why MAP3K7 is selectively vulnerable to SF3B1-driven mis-splicing is unclear\", \"Direct GATA1 regulatory mechanism downstream of p38 not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the structural basis of CSCF pathogenicity by showing the Val50Ala variant disrupts ATP binding and kinase-domain structure to reduce autophosphorylation, with TGF-\\u03b2 partially restoring downstream signaling, distinguishing it from FMD2 variants.\",\n      \"evidence\": \"HEK293T overexpression with phosphorylation Western blots, 3D modeling, and TGF-\\u03b2 rescue\",\n      \"pmids\": [\"42040894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous patient-cell validation not performed\", \"Mechanism of differential downstream pathway effects vs FMD2 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed MAP3K7 as a cancer-intrinsic cytoprotective checkpoint and a regulator of genomic integrity: it integrates TNF/IFN\\u03b3 to suppress RIPK1/Caspase-8 inflammatory death by stabilizing cFLIP, and phosphorylates EphA2-Ser897 to control RAD51 and prevent cGAS-STING activation.\",\n      \"evidence\": \"Kinome CRISPR screen, KO/inhibition, and syngeneic tumor models (preprint); proteomics, kinase assays, and GEMM (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.09.652721\", \"bio_10.1101_2025.10.08.681226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Findings reside in preprints not yet peer-reviewed\", \"Direct EphA2 and cFLIP phosphorylation/degradation steps require independent confirmation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked MAP3K7 loss to enhanced anti-tumor immunity, showing co-loss with CHD1 potentiates IFN-\\u03b3 responses and sensitizes tumors to T-cell killing and checkpoint blockade.\",\n      \"evidence\": \"Genome-wide CRISPR screens in tumoroid\\u2013T cell co-cultures and syngeneic melanoma model\",\n      \"pmids\": [\"41564866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MAP3K7 normally restrains IFN-\\u03b3 transcriptional output not fully defined\", \"Contribution of MAP3K7 loss independent of CHD1 not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how MAP3K7 integrates its many regulatory inputs (TAB adaptors, TRIM31 ubiquitination, iRhom2, transcript splicing) to select among its divergent downstream outputs across distinct tissues and disease contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of context-dependent substrate selection\", \"Direct phosphorylation targets in most contexts remain unmapped\", \"Structural basis of differential signaling between disease variants undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 6, 19, 21]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 6, 21]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 8, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 15, 20, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 17, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"TAK1-TAB1-TAB2 complex\"],\n    \"partners\": [\"TAB1\", \"TAB2\", \"TRIM31\", \"iRhom2\", \"IKBKB\", \"EphA2\", \"CARMA1\", \"BCL10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}