{"gene":"MET","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1986,"finding":"The MET oncogene was activated in vitro by chromosomal translocation fusing the TPR (translocated promoter region) locus on chromosome 1 to the MET proto-oncogene locus on chromosome 7q21-31, generating a hybrid 5.0 kb transcript (Tpr-Met) that acts as a constitutively active oncogene. MNNG carcinogen treatment of HOS cells caused this chromosomal rearrangement.","method":"Southern blotting, RNA expression analysis, chromosomal mapping, NIH 3T3 transformation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular characterization of oncogene activation mechanism with multiple orthogonal methods and functional transformation assay; foundational paper replicated extensively","pmids":["2423252"],"is_preprint":false},{"year":1989,"finding":"The c-MET proto-oncogene encodes a heterodimeric receptor tyrosine kinase (p190) comprising a 50 kDa alpha chain disulfide-linked to a 145 kDa beta chain (alpha-beta complex). High tyrosine kinase activity of p190 was identified in gastric tumor cell line GTL-16, accompanied by MET gene amplification and overexpression.","method":"Anti-phosphotyrosine immunoprecipitation, non-reducing SDS-PAGE, protein characterization, Southern blotting for gene amplification","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical characterization of protein structure and kinase activity; foundational paper with multiple orthogonal methods","pmids":["2541345"],"is_preprint":false},{"year":1993,"finding":"HGF/SF stimulation of the c-Met receptor activates PI-3 kinase (85 kDa subunit phosphorylated on tyrosine, PI-3K activity associates with c-Met receptor), GAP, PLC-gamma, Src, and MAP kinase as primary signal transduction targets within 10-15 minutes. PI-3 kinase association with c-Met is rapid and direct.","method":"In vitro kinase assays, phosphotyrosine immunoprecipitation, biochemical fractionation, signal transduction assays in cell culture","journal":"EXS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration of substrate phosphorylation and receptor-kinase association; single lab but multiple substrates characterized","pmids":["8380734"],"is_preprint":false},{"year":1996,"finding":"Ets transcription factors (specifically Ets1) transcriptionally upregulate MET expression by binding to four putative Ets binding sites within the first 300 bp of the MET promoter. Ets1 co-expression enhanced MET promoter activity; Ets decoy oligonucleotides reduced Met protein levels; Met activation in turn induces ETS1 mRNA, forming a positive feedback loop.","method":"5' deletion analysis of MET promoter, transient co-transfection/reporter assays, stable Ets1 transfection, decoy oligonucleotides, Western blotting","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (promoter deletion, co-transfection, stable overexpression, decoy inhibition) in single study establishing transcriptional mechanism","pmids":["8934537"],"is_preprint":false},{"year":2003,"finding":"MET signaling drives tubulogenesis via recruitment of the Gab1 adaptor protein and its effector SHP2 tyrosine phosphatase, which are crucial for sustained ERK/MAP kinase pathway activation, epithelial morphogenesis, and dissociation of adherens junctions, in addition to stimulating cellular motility, survival, and proliferation.","method":"Review synthesizing branching morphogenesis assays in 3D gels, genetic epistasis using dominant-negative constructs, biochemical signaling studies in epithelial cells","journal":"Trends in cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review paper synthesizing multiple experimental findings from the field; Gab1/SHP2/ERK pathway placement supported by functional genetics","pmids":["12791299"],"is_preprint":false},{"year":2004,"finding":"Activated Met receptor undergoes rapid endocytosis and ubiquitin-dependent sorting to the lysosomal degradative pathway. Ubiquitination of Met through the E3 ligase Cbl is required for receptor downregulation. A mutant receptor defective in Cbl binding is able to transform cells, linking impaired trafficking/degradation to oncogenic activation.","method":"Endocytic trafficking assays, ubiquitination assays, mutant receptor analysis, cell transformation assays","journal":"Current topics in microbiology and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic studies linking Cbl-mediated ubiquitination to receptor downregulation and transformation; replicated across labs","pmids":["15645709"],"is_preprint":false},{"year":2005,"finding":"The cytoplasmic C-terminal region of Met acts as a multisubstrate docking site recruiting Grb2, Gab1, STAT3, Shc, SHIP-1, and Src via their PH, PTB, SH2, and SH3 domains. Crystal structure of the Met tyrosine kinase domain provides the molecular framework for understanding substrate specificity.","method":"Crystal structure determination, structural analysis of kinase domain, domain interaction studies","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure described but this is a review paper synthesizing structural data; single structural source cited","pmids":["16132696"],"is_preprint":false},{"year":2008,"finding":"Three miRNAs (miR-34b, miR-34c, and miR-199a*) negatively regulate MET expression at the translational level. Inhibition of these miRNAs using antagomiRs increased MET protein levels; exogenous expression of these miRNAs in cancer cells blocked MET-induced signal transduction and the invasive growth program, and reduced MET-induced migratory ability of melanoma-derived primary cells.","method":"AntagomiR knockdown, miRNA overexpression, Western blotting, signal transduction assays, cell migration assays, MET protein quantification","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with multiple orthogonal methods demonstrating post-transcriptional regulation of MET by specific miRNAs","pmids":["19074879"],"is_preprint":false},{"year":2010,"finding":"Acquired resistance to MET small-molecule inhibitors (PHA-665752, JNJ38877605) in MET-addicted cells occurs through MET gene amplification leading to increased expression and constitutive phosphorylation, followed by amplification and overexpression of wild-type KRAS. KRAS amplification causes progressive loss of MET dependence and acquisition of KRAS dependence.","method":"In vitro selection of resistant cells with increasing inhibitor concentrations, gene copy number analysis, Western blotting for phosphorylation, cell viability assays, multiple cell lines and two different inhibitors","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic resistance pathway established using two independent inhibitors across multiple cell lines with orthogonal genetic and biochemical methods","pmids":["20841479"],"is_preprint":false},{"year":2010,"finding":"PAX3 and SOX10 directly activate MET expression in melanoma. PAX3 binds elements in the MET promoter independently; SOX10 synergistically activates MET expression with PAX3 or MITF but does not directly activate MET alone. Two pathways exist for PAX3-mediated MET induction: direct activation of the gene, and indirect regulation through MITF.","method":"MET promoter binding assays, reporter gene assays, co-transfection experiments, chromatin immunoprecipitation, melanoma cell line analysis","journal":"Pigment cell & melanoma research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding and reporter assays establishing transcriptional regulation; single lab with multiple methods","pmids":["20067553"],"is_preprint":false},{"year":2011,"finding":"In MET-addicted cancer cells, Ron kinase is specifically transphosphorylated by activated Met (not by other constitutively active RTKs including EGFR or HER2). Ron phosphorylation is suppressed by Met-specific kinase inhibitors and by antibody-induced shedding of Met from the cell surface. shRNA silencing of RON in MET-addicted cells decreased proliferation, clonogenic activity in vitro, and tumorigenicity in vivo.","method":"Co-immunoprecipitation, kinase inhibitor treatment, antibody-induced receptor shedding, shRNA knockdown, in vitro proliferation/clonogenicity assays, in vivo tumorigenicity assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, kinase inhibitors, antibody shedding, shRNA KD, in vivo) establishing specific transphosphorylation mechanism","pmids":["21212418"],"is_preprint":false},{"year":2011,"finding":"Mutant Met receptors bearing kinase-activating mutations (unlike wild-type) circumvent ubiquitin-dependent lysosomal degradation and instead recycle to the plasma membrane via GGA3 adaptor protein recruitment. This recycling is mediated through GGA3 interaction with activated Arf6 and indirect binding to phosphorylated Met through adaptor protein Crk. Mutant receptors elicit enhanced signaling from endosomes critical for cell motility and tumorigenesis.","method":"Endocytic trafficking analysis, receptor recycling assays, adaptor protein interaction studies","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review/perspective synthesizing new mechanistic data on endosomal recycling pathway; GGA3/Arf6/Crk pathway supported by experimental data cited","pmids":["21917713"],"is_preprint":false},{"year":2011,"finding":"Crystal structures of Met in complex with L. monocytogenes InlB suggest that Met dimerization is mediated by a dimer contact of the ligand. Structural comparison with HGF/SF reveals parallels and differences in Met activation mechanisms.","method":"X-ray crystallography of Met-InlB complex, structural comparison","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure established with bacterial ligand; mechanistic parallels to physiological HGF/SF activation are inferred by structural comparison, not directly demonstrated","pmids":["21242015"],"is_preprint":false},{"year":2014,"finding":"PAX3 and ETS1 directly interact and synergistically activate MET expression through the 300 bp 5' proximal MET promoter, which contains a PAX3 response element and two ETS1 consensus motifs. ETS1 activates MET via PAX3-dependent and PAX3-independent mechanisms. HGF-dependent ETS1 activation enhances MET expression indirectly, creating a positive feedback loop. Dominant-negative ETS1 reduces melanoma cell growth in culture and in vivo.","method":"Promoter reporter assays, co-immunoprecipitation of PAX3-ETS1 interaction, ChIP, siRNA knockdown, dominant-negative constructs, in vivo tumor growth assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein-protein interaction demonstrated by Co-IP, promoter mechanism established by multiple binding site analyses, in vivo functional validation","pmids":["25531327"],"is_preprint":false},{"year":2015,"finding":"Somatic splice site alterations at MET exon 14 (METex14) result in exon skipping, loss of the juxtamembrane domain (which contains a negative regulatory region and the Cbl E3 ligase binding site Y1003), and constitutive MET kinase activation leading to oncogenic transformation in vitro. Cells harboring METex14 alterations are sensitive to MET inhibitors.","method":"Comprehensive genomic profiling of 38,028 tumor samples, functional in vitro studies of METex14 alterations, MET inhibitor sensitivity assays","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanism of activation (loss of juxtamembrane regulatory domain) established with functional in vitro validation across large patient cohort; multiple labs have replicated clinical findings","pmids":["25971938"],"is_preprint":false},{"year":2015,"finding":"MET kinase domain fusions (TRIM4-MET and ZKSCAN1-MET) constitutively activate MAPK, PI3K, and PLCγ1 signaling pathways. These fusion kinases are blocked by MET inhibitors cabozantinib and PF-04217903 at nanomolar concentrations.","method":"Identification of MET fusions by genomic analysis, functional characterization of fusion proteins with western blotting for downstream signaling, MET inhibitor treatment assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional characterization of two fusion proteins with signaling pathway analysis and inhibitor sensitivity; single study","pmids":["26013381"],"is_preprint":false},{"year":2015,"finding":"A missense mutation c.2521T>G (p.F841V) in MET (encoding the hepatocyte growth factor receptor) is associated with autosomal recessive non-syndromic hearing loss (DFNB97) in humans, mapped to chromosome 7q31.2, establishing MET function in auditory system development.","method":"Homozygosity mapping with 1 million SNP array, whole-exome sequencing, Sanger confirmation, cosegregation analysis, absence from 800 control chromosomes","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic linkage and exome sequencing identify causal mutation; functional validation is indirect (prediction programs) without in vitro mechanistic follow-up","pmids":["25941349"],"is_preprint":false},{"year":2015,"finding":"PTPRZ1-MET (ZM) fusion proteins preserve fundamental properties of wild-type MET with respect to processing and dimerization, and enhance MET phosphorylation in both HGF-dependent and HGF-independent manners. ZM fusions increase MET mRNA expression levels.","method":"Western blotting, phosphorylation analysis, dimerization assays, mRNA expression analysis in ZM fusion-carrying patient samples and cell models","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization of fusion protein properties including HGF-independent activation; single lab","pmids":["25935522"],"is_preprint":false},{"year":2016,"finding":"MET signaling in keratinocytes activates EGFR through autocrine EGFR ligand synthesis and release, mediated by the kinase SRC, the pseudoproteases iRhom1 and iRhom2, and the metallopeptidase ADAM17. Pharmacological EGFR inhibition caused regression of MET-driven spontaneous squamous tumors.","method":"Transgenic MT-HGF mouse model, keratinocyte culture studies, Western blotting for signaling, pharmacological inhibition of EGFR/SRC/ADAM17, gene expression profiling","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanism established in both in vitro keratinocyte models and in vivo transgenic tumor models with pharmacological rescue experiments; multiple pathway components identified","pmids":["27330189"],"is_preprint":false},{"year":2019,"finding":"In MET-amplified cancer cells, MET inhibition counteracts IFN-γ-induced PD-L1/PD-L2 upregulation. JAK2 and MET physically associate in the same signaling complex in a MET phosphorylation-dependent manner. MET inhibitors (JNJ-605, MvDN30) neutralize JAK/STAT1 signaling downstream of the IFN-γ receptor, preventing PD-1 ligand induction.","method":"Co-immunoprecipitation of MET-JAK2 complex, PD-L1/PD-L2 expression analysis, MET inhibitor treatment, signaling pathway analysis in MET-amplified cell lines and patient-derived tumor organoids","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing MET-JAK2 complex, validated in organoid models, multiple inhibitors and cell lines tested","pmids":["30723303"],"is_preprint":false},{"year":2020,"finding":"METex14 skipping results in loss of the juxtamembrane domain, retaining HGF affinity but eliminating negative regulatory function, leading to receptor accumulation on the cell surface and prolonged HGF-dependent activation.","method":"Review synthesizing functional studies of METex14 deletion consequences on receptor biology","journal":"Cancer treatment reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic interpretation supported by functional studies reported across multiple laboratories; single review paper but based on replicated experimental findings","pmids":["32334240"],"is_preprint":false},{"year":2021,"finding":"ENO1 (alpha-enolase) directly interacts with MET (HGFR) and activates HGFR signaling via increased phosphorylation of HGFR. This interaction activates Wnt coreceptor LRP5/6, decreases GSK3β activity via Src-PI3K-AKT signaling, inactivates the β-catenin destruction complex, and upregulates SLUG and β-catenin to promote EMT and lung cancer metastasis.","method":"Co-immunoprecipitation of ENO1-HGFR, Western blotting for phosphorylation, knockdown/overexpression studies, in vivo orthotopic and tail-vein injection models, anti-ENO1 antibody treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP establishing ENO1-HGFR interaction, mechanistic pathway characterized with multiple downstream readouts, validated in vivo","pmids":["34145039"],"is_preprint":false},{"year":2021,"finding":"MET-deficient neutrophils (MRP8-Cre MET-LoxP mice) show reduced severity of DSS-induced colitis, decreased TH17 cell numbers, and decreased IL-1β production, establishing that neutrophilic HGF-MET signaling promotes intestinal inflammation through IL-1β-mediated TH17 expansion.","method":"Conditional knockout mice (MRP8-Cre MET-LoxP), DSS colitis model, flow cytometry for immune cell populations, cytokine quantification","journal":"Journal of Crohn's & colitis","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockout with well-defined phenotypic and mechanistic readouts establishing MET function in neutrophil-mediated inflammation","pmids":["32556102"],"is_preprint":false},{"year":2021,"finding":"CYP1A2 suppresses HGF/MET signaling by binding to HIF-1α (transcriptional activator of MET) and inducing ubiquitin-mediated degradation of HIF-1α, thereby inhibiting HIF-1α-mediated MET transcription. CYP1A2 also decreases HGF levels, reducing MET activation.","method":"Co-immunoprecipitation of CYP1A2-HIF-1α interaction, ubiquitination assays, Western blotting, CYP1A2 overexpression/knockdown studies, in vivo tumor model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes binding, ubiquitination assay establishes degradation mechanism; single lab study","pmids":["33500715"],"is_preprint":false},{"year":2023,"finding":"Circular MET RNA (circMET) encodes a 404-amino-acid MET variant (MET404) whose translation is facilitated by the m6A reader YTHDF2. MET404 directly interacts with the MET beta subunit forming a constitutively activated MET receptor complex whose activity does not require HGF stimulation. Genetic ablation of circMET in mice attenuates MET signaling; MET404 knock-in plus P53 knockout in mouse astrocytes initiates GBM tumorigenesis.","method":"circMET genetic ablation in mice, MET404 knock-in mouse model, co-immunoprecipitation of MET404-MET beta subunit, neutralizing antibody treatment, in vitro and in vivo tumorigenicity assays, YTHDF2 functional studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including in vivo genetic models (KI/KO), direct protein-protein interaction by Co-IP, neutralizing antibody validation, and mechanistic characterization of HGF-independent activation","pmids":["37491377"],"is_preprint":false},{"year":2023,"finding":"EpCAM extracellular domain (EpEX) physically binds to MET (HGFR) and activates downstream ERK and FAK-AKT signaling, stabilizes active β-catenin and Snail proteins via GSK3β inactivation, and promotes EMT and metastatic potential. EpEX and HGF cooperatively mediate HGFR signaling.","method":"Co-immunoprecipitation, ELISA, FRET analysis of EpEX-HGFR interaction, Western blotting for downstream signaling, in vivo metastasis models (tail vein injection and orthotopic)","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — three orthogonal methods (Co-IP, ELISA, FRET) establishing direct EpEX-HGFR interaction, mechanistic pathway characterized with in vivo validation","pmids":["37543570"],"is_preprint":false}],"current_model":"MET encodes a heterodimeric (alpha-beta) receptor tyrosine kinase for HGF/SF; upon ligand binding or oncogenic activation (chromosomal translocation generating Tpr-Met, gene amplification, exon 14 skipping losing the juxtamembrane Cbl-binding negative regulatory domain, or kinase domain fusions), MET autophosphorylates and recruits a multi-substrate docking complex (Gab1, Grb2, SHP2, STAT3, Shc, Src, PI3K) to activate MAPK/ERK, PI3K/AKT, and PLCγ1 pathways driving proliferation, motility, invasion, and tubulogenesis; MET is downregulated via Cbl E3-ligase-mediated ubiquitination and lysosomal degradation, a process circumvented by activating mutations that redirect the receptor to endosomal recycling; MET transcription is driven by Ets1/PAX3/SOX10 transcription factors and negatively post-transcriptionally regulated by miR-34b/c and miR-199a*; MET also forms signaling complexes with JAK2, EGFR, and Ron, transphosphorylating Ron in MET-addicted cells and transactivating EGFR via SRC/iRhom/ADAM17-mediated ligand shedding, while a circRNA-encoded MET variant (MET404) constitutively activates MET signaling independent of HGF."},"narrative":{"mechanistic_narrative":"MET encodes a heterodimeric (α-β) receptor tyrosine kinase whose activation drives proliferation, motility, invasion, and epithelial tubulogenesis, and which is a recurrent oncogenic driver across multiple cancers [PMID:2541345, PMID:12791299]. Originally identified through a carcinogen-induced chromosomal translocation fusing the TPR locus to MET to generate the constitutively active Tpr-Met oncogene [PMID:2423252], the receptor is a p190 complex of a 50 kDa α chain disulfide-linked to a 145 kDa β chain with intrinsic tyrosine kinase activity that is amplified and constitutively phosphorylated in tumor cells [PMID:2541345]. Upon activation MET autophosphorylates and uses its C-terminal multisubstrate docking site to recruit Grb2, Gab1, SHP2, STAT3, Shc, SHIP-1, and Src, engaging PI3K, PLCγ, Src, and the ERK/MAP kinase cascade to sustain morphogenesis and survival signaling [PMID:8380734, PMID:12791299, PMID:16132696]. Receptor output is normally limited by Cbl-mediated ubiquitination and lysosomal degradation; oncogenic activation circumvents this control, with exon 14 skipping deleting the juxtamembrane Cbl-binding negative regulatory domain to prolong signaling, and kinase-activating mutants redirected to GGA3-dependent endosomal recycling that enhances signaling [PMID:15645709, PMID:21917713, PMID:25971938, PMID:32334240]. Diverse oncogenic activation modes converge on this kinase, including MET amplification, METex14 skipping, kinase-domain fusions (TRIM4-MET, ZKSCAN1-MET, PTPRZ1-MET) that constitutively fire MAPK/PI3K/PLCγ1, and a circRNA-encoded MET404 variant that binds the MET β subunit to assemble an HGF-independent active receptor [PMID:25971938, PMID:26013381, PMID:25935522, PMID:37491377]. MET transcription is driven by Ets1, PAX3, and SOX10 through the proximal promoter, and is restrained post-transcriptionally by miR-34b/c and miR-199a* [PMID:8934537, PMID:19074879, PMID:20067553, PMID:25531327]. The receptor cross-talks with other signaling systems, transphosphorylating Ron in MET-addicted cells, complexing with JAK2 to control IFN-γ-induced PD-L1/PD-L2 induction, and transactivating EGFR via SRC/iRhom/ADAM17-mediated ligand shedding; binding partners ENO1 and EpCAM (EpEX) further amplify MET signaling toward β-catenin-driven EMT and metastasis [PMID:21212418, PMID:27330189, PMID:30723303, PMID:34145039, PMID:37543570]. Beyond cancer, MET function extends to auditory development, where a missense mutation causes autosomal recessive non-syndromic hearing loss (DFNB97), and to neutrophil-driven intestinal inflammation through IL-1β-mediated TH17 expansion [PMID:25941349, PMID:32556102]. Acquired resistance to MET inhibitors arises through MET amplification and subsequent KRAS amplification that shifts cells to KRAS dependence [PMID:20841479].","teleology":[{"year":1986,"claim":"Established that MET can be activated as an oncogene, defining the first mechanism by which a chromosomal rearrangement creates a constitutively active MET kinase.","evidence":"Southern blotting, chromosomal mapping, and NIH 3T3 transformation of carcinogen-treated HOS cells generating the Tpr-Met fusion","pmids":["2423252"],"confidence":"High","gaps":["Did not characterize the normal receptor structure or ligand","Frequency of TPR-MET in spontaneous human tumors not addressed"]},{"year":1989,"claim":"Defined MET as a heterodimeric α-β receptor tyrosine kinase and linked gene amplification to constitutive kinase activity in tumor cells.","evidence":"Anti-phosphotyrosine IP, non-reducing SDS-PAGE, and amplification analysis in the GTL-16 gastric line","pmids":["2541345"],"confidence":"High","gaps":["Downstream substrates not yet mapped","Ligand-dependent activation not characterized"]},{"year":1993,"claim":"Mapped the immediate signaling output of HGF-activated MET, identifying the effectors that transduce the receptor's mitogenic and motogenic signals.","evidence":"In vitro kinase assays and phosphotyrosine IP showing rapid PI3K, GAP, PLCγ, Src, and MAPK engagement","pmids":["8380734"],"confidence":"Medium","gaps":["Direct vs adaptor-mediated recruitment not resolved","Single-lab biochemistry"]},{"year":1996,"claim":"Showed how MET expression is transcriptionally driven, identifying Ets1 as a promoter-binding activator in a positive feedback loop with MET signaling.","evidence":"MET promoter deletion, reporter co-transfection, stable Ets1 overexpression, and decoy oligonucleotides","pmids":["8934537"],"confidence":"High","gaps":["Tissue specificity of Ets1 control unclear","Cooperating factors not yet defined"]},{"year":2003,"claim":"Connected MET signaling to epithelial tubulogenesis through the Gab1/SHP2 module required for sustained ERK activation.","evidence":"Review synthesizing 3D branching morphogenesis assays and dominant-negative epistasis","pmids":["12791299"],"confidence":"Medium","gaps":["Review-level synthesis rather than single primary dataset","Quantitative contribution of each effector to morphogenesis not parsed"]},{"year":2004,"claim":"Established Cbl-mediated ubiquitination and lysosomal degradation as the negative control on MET, and linked its loss to transformation.","evidence":"Endocytic trafficking, ubiquitination assays, and Cbl-binding-defective mutant transformation assays","pmids":["15645709"],"confidence":"Medium","gaps":["Endosomal signaling output not quantified here","Recycling fate of escapee receptors not yet defined"]},{"year":2005,"claim":"Defined the C-terminal multisubstrate docking site structurally and as the hub recruiting the adaptor/effector ensemble.","evidence":"Crystal structure of the MET kinase domain with domain-interaction analysis (review)","pmids":["16132696"],"confidence":"Medium","gaps":["Structural source synthesized in a review","Phosphosite-specific binding stoichiometry not mapped"]},{"year":2008,"claim":"Identified post-transcriptional restraint of MET, showing specific miRNAs limit receptor levels and the invasive growth program.","evidence":"AntagomiR knockdown and miRNA overexpression with migration and signaling readouts in cancer/melanoma cells","pmids":["19074879"],"confidence":"High","gaps":["Endogenous miRNA dosage in tumors not established","Other 3'UTR regulators not surveyed"]},{"year":2010,"claim":"Defined a clinically relevant resistance mechanism to MET inhibitors, showing oncogene switching from MET to KRAS.","evidence":"In vitro selection with two MET inhibitors across lines, copy-number and phosphorylation analysis","pmids":["20841479"],"confidence":"High","gaps":["Whether KRAS bypass occurs in patients not tested here","Other bypass routes not enumerated"]},{"year":2010,"claim":"Extended transcriptional control of MET to the melanocyte lineage, defining PAX3/SOX10/MITF cooperation at the promoter.","evidence":"Promoter binding, reporter, co-transfection, and ChIP in melanoma cells","pmids":["20067553"],"confidence":"Medium","gaps":["Relative contribution of direct vs MITF-indirect routes not quantified","Single-lab"]},{"year":2011,"claim":"Showed how activating mutants evade degradation by GGA3/Arf6/Crk-mediated endosomal recycling, linking trafficking to oncogenic signaling.","evidence":"Endocytic trafficking and recycling assays with adaptor-interaction studies","pmids":["21917713"],"confidence":"Medium","gaps":["Synthesized as a perspective","Endosomal signaling effectors not fully defined"]},{"year":2011,"claim":"Established MET-driven transphosphorylation of Ron as a functional cross-talk required for the malignant phenotype in MET-addicted cells.","evidence":"Co-IP, kinase inhibitors, antibody-induced shedding, RON shRNA, and in vivo tumorigenicity","pmids":["21212418"],"confidence":"High","gaps":["Stoichiometry of MET-Ron complex not defined","Generality beyond MET-addicted lines unclear"]},{"year":2011,"claim":"Provided structural insight into MET dimerization via the bacterial ligand InlB, with inferred parallels to HGF/SF activation.","evidence":"X-ray crystallography of MET-InlB complex and structural comparison","pmids":["21242015"],"confidence":"Medium","gaps":["Parallels to physiological HGF activation inferred, not directly shown","HGF-bound dimer geometry not resolved here"]},{"year":2014,"claim":"Showed direct PAX3-ETS1 protein interaction and synergy at the proximal MET promoter, integrating two transcriptional inputs into a feedback loop with functional tumor relevance.","evidence":"Reporter assays, Co-IP, ChIP, siRNA, dominant-negative ETS1, and in vivo tumor growth","pmids":["25531327"],"confidence":"High","gaps":["Promoter architecture in non-melanoma contexts not tested","Chromatin state dependence not addressed"]},{"year":2015,"claim":"Defined METex14 skipping as a recurrent activating event that deletes the juxtamembrane Cbl-binding regulatory domain and confers inhibitor sensitivity.","evidence":"Genomic profiling of 38,028 tumors with functional in vitro transformation and inhibitor assays","pmids":["25971938"],"confidence":"High","gaps":["Quantitative degradation defect not directly measured here","Tissue-specific frequency drivers unclear"]},{"year":2015,"claim":"Established MET kinase-domain fusions as constitutive activators of MAPK/PI3K/PLCγ1 amenable to MET inhibition.","evidence":"Genomic identification and functional signaling/inhibitor characterization of TRIM4-MET and ZKSCAN1-MET","pmids":["26013381"],"confidence":"Medium","gaps":["Single study","In vivo tumorigenicity of these fusions not shown"]},{"year":2015,"claim":"Characterized PTPRZ1-MET fusion processing and HGF-independent activation, broadening the fusion-driven activation repertoire.","evidence":"Western blotting, phosphorylation, dimerization, and mRNA analysis in ZM-carrying samples/models","pmids":["25935522"],"confidence":"Medium","gaps":["Single-lab","Downstream pathway selectivity not mapped"]},{"year":2015,"claim":"Linked MET to a Mendelian phenotype, identifying a causal missense mutation in autosomal recessive non-syndromic hearing loss (DFNB97).","evidence":"Homozygosity mapping, whole-exome sequencing, Sanger confirmation, and cosegregation in a family","pmids":["25941349"],"confidence":"Medium","gaps":["Functional consequence of p.F841V validated only by prediction","Mechanism in auditory development not established"]},{"year":2016,"claim":"Defined MET-to-EGFR transactivation via SRC/iRhom/ADAM17-mediated ligand shedding, revealing a therapeutically exploitable cross-talk in MET-driven tumors.","evidence":"MT-HGF transgenic mice, keratinocyte cultures, and pharmacological EGFR/SRC/ADAM17 inhibition with tumor regression","pmids":["27330189"],"confidence":"High","gaps":["Generality across epithelial tissues not established","Relative weight of autocrine EGFR ligands not parsed"]},{"year":2019,"claim":"Established a physical MET-JAK2 complex controlling IFN-γ-induced PD-L1/PD-L2, linking MET to immune-evasion signaling.","evidence":"Reciprocal Co-IP, MET inhibitors, and PD-ligand analysis in MET-amplified lines and patient-derived organoids","pmids":["30723303"],"confidence":"High","gaps":["In vivo immune consequences not directly tested","Direct vs indirect MET-JAK2 contact unresolved"]},{"year":2021,"claim":"Identified ENO1 as a direct MET-activating partner driving Wnt/β-catenin-dependent EMT and metastasis.","evidence":"Co-IP, knockdown/overexpression, anti-ENO1 antibody, and in vivo orthotopic/tail-vein models","pmids":["34145039"],"confidence":"High","gaps":["Structural basis of ENO1-MET binding unknown","Generality beyond lung cancer untested"]},{"year":2021,"claim":"Established a non-cancer in vivo role for MET in neutrophils, promoting intestinal inflammation through IL-1β-driven TH17 expansion.","evidence":"MRP8-Cre MET-LoxP conditional knockout in DSS colitis with flow cytometry and cytokine readouts","pmids":["32556102"],"confidence":"High","gaps":["Molecular link from MET to IL-1β not detailed","Relevance to human IBD not established"]},{"year":2021,"claim":"Defined CYP1A2 as an upstream suppressor of MET transcription by degrading HIF-1α, revealing a metabolic regulator of HGF/MET output.","evidence":"Co-IP, ubiquitination assays, CYP1A2 gain/loss-of-function, and in vivo tumor model","pmids":["33500715"],"confidence":"Medium","gaps":["Single-lab","HIF-1α-independent effects on HGF not dissected"]},{"year":2023,"claim":"Showed that a circRNA-encoded MET404 variant assembles an HGF-independent active receptor, defining a non-canonical mode of constitutive MET activation in gliomagenesis.","evidence":"circMET ablation and MET404 knock-in mice, MET404-MET β Co-IP, neutralizing antibody, and tumorigenicity assays with YTHDF2 studies","pmids":["37491377"],"confidence":"High","gaps":["Frequency of MET404 across tumor types unknown","Structural basis of MET404-β subunit activation not resolved"]},{"year":2023,"claim":"Identified EpCAM ectodomain (EpEX) as a direct MET ligand-like partner cooperating with HGF to drive EMT and metastasis.","evidence":"Co-IP, ELISA, FRET, downstream signaling Westerns, and in vivo metastasis models","pmids":["37543570"],"confidence":"High","gaps":["Binding interface not mapped","Relative contribution of EpEX vs HGF in vivo not quantified"]},{"year":null,"claim":"How the diverse activation modes (amplification, METex14, fusions, MET404, non-HGF partners) differentially shape receptor trafficking, effector wiring, and therapeutic 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triple-negative breast cancer.","date":"2014","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/24556651","citation_count":35,"is_preprint":false},{"pmid":"33500715","id":"PMC_33500715","title":"CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33500715","citation_count":34,"is_preprint":false},{"pmid":"25531327","id":"PMC_25531327","title":"PAX3 and ETS1 synergistically activate MET expression in melanoma cells.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25531327","citation_count":34,"is_preprint":false},{"pmid":"32556102","id":"PMC_32556102","title":"Neutrophilic HGF-MET Signalling Exacerbates Intestinal Inflammation.","date":"2020","source":"Journal of Crohn's & colitis","url":"https://pubmed.ncbi.nlm.nih.gov/32556102","citation_count":33,"is_preprint":false},{"pmid":"15261136","id":"PMC_15261136","title":"Met decoys: will cancer take the bait?","date":"2004","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/15261136","citation_count":31,"is_preprint":false},{"pmid":"21242015","id":"PMC_21242015","title":"Structural insights into Met receptor activation.","date":"2011","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21242015","citation_count":30,"is_preprint":false},{"pmid":"36829199","id":"PMC_36829199","title":"Identification of MET fusions as novel therapeutic targets sensitive to MET inhibitors in lung cancer.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36829199","citation_count":30,"is_preprint":false},{"pmid":"26600931","id":"PMC_26600931","title":"Clinical significance of MET in gastric cancer.","date":"2015","source":"World journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26600931","citation_count":30,"is_preprint":false},{"pmid":"24393368","id":"PMC_24393368","title":"Expressions and clinical significances of c-MET, p-MET and E2f-1 in human gastric carcinoma.","date":"2014","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/24393368","citation_count":30,"is_preprint":false},{"pmid":"8380734","id":"PMC_8380734","title":"Signal transduction in c-met mediated motogenesis.","date":"1993","source":"EXS","url":"https://pubmed.ncbi.nlm.nih.gov/8380734","citation_count":29,"is_preprint":false},{"pmid":"19397476","id":"PMC_19397476","title":"Inhibition of HGF/MET as therapy for malignancy.","date":"2009","source":"Expert opinion on therapeutic targets","url":"https://pubmed.ncbi.nlm.nih.gov/19397476","citation_count":29,"is_preprint":false},{"pmid":"11523050","id":"PMC_11523050","title":"Absence of tpr-met and expression of c-met in human gastric mucosa and carcinoma.","date":"2001","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11523050","citation_count":29,"is_preprint":false},{"pmid":"26366398","id":"PMC_26366398","title":"MET deregulation in breast cancer.","date":"2015","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26366398","citation_count":28,"is_preprint":false},{"pmid":"36521334","id":"PMC_36521334","title":"Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors.","date":"2022","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/36521334","citation_count":28,"is_preprint":false},{"pmid":"21917713","id":"PMC_21917713","title":"Met receptor: a moving target.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21917713","citation_count":27,"is_preprint":false},{"pmid":"27157666","id":"PMC_27157666","title":"Sequence-defined cMET/HGFR-targeted Polymers as Gene Delivery Vehicles for the Theranostic Sodium Iodide Symporter (NIS) Gene.","date":"2016","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/27157666","citation_count":27,"is_preprint":false},{"pmid":"26097886","id":"PMC_26097886","title":"Retrospective Review of MET Gene Mutations.","date":"2015","source":"Oncoscience","url":"https://pubmed.ncbi.nlm.nih.gov/26097886","citation_count":27,"is_preprint":false},{"pmid":"27330189","id":"PMC_27330189","title":"MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis.","date":"2016","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/27330189","citation_count":27,"is_preprint":false},{"pmid":"31476283","id":"PMC_31476283","title":"The Role of MET in Melanoma and Melanocytic Lesions.","date":"2019","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31476283","citation_count":26,"is_preprint":false},{"pmid":"34031544","id":"PMC_34031544","title":"When the MET receptor kicks in to resist targeted therapies.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34031544","citation_count":26,"is_preprint":false},{"pmid":"20237428","id":"PMC_20237428","title":"The Met receptor tyrosine kinase and basal breast cancer.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20237428","citation_count":25,"is_preprint":false},{"pmid":"28586107","id":"PMC_28586107","title":"Are energy and protein requirements met in hospital?","date":"2017","source":"Journal of human nutrition and dietetics : the official journal of the British Dietetic Association","url":"https://pubmed.ncbi.nlm.nih.gov/28586107","citation_count":25,"is_preprint":false},{"pmid":"22235915","id":"PMC_22235915","title":"Met interacts with EGFR and Ron in canine osteosarcoma.","date":"2011","source":"Veterinary and comparative oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22235915","citation_count":25,"is_preprint":false},{"pmid":"25992367","id":"PMC_25992367","title":"MicroRNA and MET in lung cancer.","date":"2015","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25992367","citation_count":24,"is_preprint":false},{"pmid":"22500688","id":"PMC_22500688","title":"Targeting the Met pathway in lung cancer.","date":"2012","source":"Expert review of anticancer therapy","url":"https://pubmed.ncbi.nlm.nih.gov/22500688","citation_count":24,"is_preprint":false},{"pmid":"32593403","id":"PMC_32593403","title":"MET receptor in oncology: From biomarker to therapeutic target.","date":"2020","source":"Advances in cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32593403","citation_count":23,"is_preprint":false},{"pmid":"22181983","id":"PMC_22181983","title":"MET and phosphorylated MET as potential biomarkers in lung cancer.","date":"2011","source":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22181983","citation_count":23,"is_preprint":false},{"pmid":"31895394","id":"PMC_31895394","title":"When robotics met fluidics.","date":"2020","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/31895394","citation_count":22,"is_preprint":false},{"pmid":"10359528","id":"PMC_10359528","title":"Amplification and overexpression of the hepatocyte growth factor receptor (HGFR/MET) in rat DMBA sarcomas.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10359528","citation_count":21,"is_preprint":false},{"pmid":"25935522","id":"PMC_25935522","title":"Enhanced expression and phosphorylation of the MET oncoprotein by glioma-specific PTPRZ1-MET fusions.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/25935522","citation_count":21,"is_preprint":false},{"pmid":"37543570","id":"PMC_37543570","title":"Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37543570","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41190,"output_tokens":6758,"usd":0.11247,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15894,"output_tokens":6687,"usd":0.123323,"stage2_stop_reason":"end_turn"},"total_usd":0.235793,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1986,\n      \"finding\": \"The MET oncogene was activated in vitro by chromosomal translocation fusing the TPR (translocated promoter region) locus on chromosome 1 to the MET proto-oncogene locus on chromosome 7q21-31, generating a hybrid 5.0 kb transcript (Tpr-Met) that acts as a constitutively active oncogene. MNNG carcinogen treatment of HOS cells caused this chromosomal rearrangement.\",\n      \"method\": \"Southern blotting, RNA expression analysis, chromosomal mapping, NIH 3T3 transformation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular characterization of oncogene activation mechanism with multiple orthogonal methods and functional transformation assay; foundational paper replicated extensively\",\n      \"pmids\": [\"2423252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"The c-MET proto-oncogene encodes a heterodimeric receptor tyrosine kinase (p190) comprising a 50 kDa alpha chain disulfide-linked to a 145 kDa beta chain (alpha-beta complex). High tyrosine kinase activity of p190 was identified in gastric tumor cell line GTL-16, accompanied by MET gene amplification and overexpression.\",\n      \"method\": \"Anti-phosphotyrosine immunoprecipitation, non-reducing SDS-PAGE, protein characterization, Southern blotting for gene amplification\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical characterization of protein structure and kinase activity; foundational paper with multiple orthogonal methods\",\n      \"pmids\": [\"2541345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"HGF/SF stimulation of the c-Met receptor activates PI-3 kinase (85 kDa subunit phosphorylated on tyrosine, PI-3K activity associates with c-Met receptor), GAP, PLC-gamma, Src, and MAP kinase as primary signal transduction targets within 10-15 minutes. PI-3 kinase association with c-Met is rapid and direct.\",\n      \"method\": \"In vitro kinase assays, phosphotyrosine immunoprecipitation, biochemical fractionation, signal transduction assays in cell culture\",\n      \"journal\": \"EXS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration of substrate phosphorylation and receptor-kinase association; single lab but multiple substrates characterized\",\n      \"pmids\": [\"8380734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Ets transcription factors (specifically Ets1) transcriptionally upregulate MET expression by binding to four putative Ets binding sites within the first 300 bp of the MET promoter. Ets1 co-expression enhanced MET promoter activity; Ets decoy oligonucleotides reduced Met protein levels; Met activation in turn induces ETS1 mRNA, forming a positive feedback loop.\",\n      \"method\": \"5' deletion analysis of MET promoter, transient co-transfection/reporter assays, stable Ets1 transfection, decoy oligonucleotides, Western blotting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (promoter deletion, co-transfection, stable overexpression, decoy inhibition) in single study establishing transcriptional mechanism\",\n      \"pmids\": [\"8934537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MET signaling drives tubulogenesis via recruitment of the Gab1 adaptor protein and its effector SHP2 tyrosine phosphatase, which are crucial for sustained ERK/MAP kinase pathway activation, epithelial morphogenesis, and dissociation of adherens junctions, in addition to stimulating cellular motility, survival, and proliferation.\",\n      \"method\": \"Review synthesizing branching morphogenesis assays in 3D gels, genetic epistasis using dominant-negative constructs, biochemical signaling studies in epithelial cells\",\n      \"journal\": \"Trends in cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review paper synthesizing multiple experimental findings from the field; Gab1/SHP2/ERK pathway placement supported by functional genetics\",\n      \"pmids\": [\"12791299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Activated Met receptor undergoes rapid endocytosis and ubiquitin-dependent sorting to the lysosomal degradative pathway. Ubiquitination of Met through the E3 ligase Cbl is required for receptor downregulation. A mutant receptor defective in Cbl binding is able to transform cells, linking impaired trafficking/degradation to oncogenic activation.\",\n      \"method\": \"Endocytic trafficking assays, ubiquitination assays, mutant receptor analysis, cell transformation assays\",\n      \"journal\": \"Current topics in microbiology and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic studies linking Cbl-mediated ubiquitination to receptor downregulation and transformation; replicated across labs\",\n      \"pmids\": [\"15645709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The cytoplasmic C-terminal region of Met acts as a multisubstrate docking site recruiting Grb2, Gab1, STAT3, Shc, SHIP-1, and Src via their PH, PTB, SH2, and SH3 domains. Crystal structure of the Met tyrosine kinase domain provides the molecular framework for understanding substrate specificity.\",\n      \"method\": \"Crystal structure determination, structural analysis of kinase domain, domain interaction studies\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure described but this is a review paper synthesizing structural data; single structural source cited\",\n      \"pmids\": [\"16132696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Three miRNAs (miR-34b, miR-34c, and miR-199a*) negatively regulate MET expression at the translational level. Inhibition of these miRNAs using antagomiRs increased MET protein levels; exogenous expression of these miRNAs in cancer cells blocked MET-induced signal transduction and the invasive growth program, and reduced MET-induced migratory ability of melanoma-derived primary cells.\",\n      \"method\": \"AntagomiR knockdown, miRNA overexpression, Western blotting, signal transduction assays, cell migration assays, MET protein quantification\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with multiple orthogonal methods demonstrating post-transcriptional regulation of MET by specific miRNAs\",\n      \"pmids\": [\"19074879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Acquired resistance to MET small-molecule inhibitors (PHA-665752, JNJ38877605) in MET-addicted cells occurs through MET gene amplification leading to increased expression and constitutive phosphorylation, followed by amplification and overexpression of wild-type KRAS. KRAS amplification causes progressive loss of MET dependence and acquisition of KRAS dependence.\",\n      \"method\": \"In vitro selection of resistant cells with increasing inhibitor concentrations, gene copy number analysis, Western blotting for phosphorylation, cell viability assays, multiple cell lines and two different inhibitors\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic resistance pathway established using two independent inhibitors across multiple cell lines with orthogonal genetic and biochemical methods\",\n      \"pmids\": [\"20841479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PAX3 and SOX10 directly activate MET expression in melanoma. PAX3 binds elements in the MET promoter independently; SOX10 synergistically activates MET expression with PAX3 or MITF but does not directly activate MET alone. Two pathways exist for PAX3-mediated MET induction: direct activation of the gene, and indirect regulation through MITF.\",\n      \"method\": \"MET promoter binding assays, reporter gene assays, co-transfection experiments, chromatin immunoprecipitation, melanoma cell line analysis\",\n      \"journal\": \"Pigment cell & melanoma research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding and reporter assays establishing transcriptional regulation; single lab with multiple methods\",\n      \"pmids\": [\"20067553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In MET-addicted cancer cells, Ron kinase is specifically transphosphorylated by activated Met (not by other constitutively active RTKs including EGFR or HER2). Ron phosphorylation is suppressed by Met-specific kinase inhibitors and by antibody-induced shedding of Met from the cell surface. shRNA silencing of RON in MET-addicted cells decreased proliferation, clonogenic activity in vitro, and tumorigenicity in vivo.\",\n      \"method\": \"Co-immunoprecipitation, kinase inhibitor treatment, antibody-induced receptor shedding, shRNA knockdown, in vitro proliferation/clonogenicity assays, in vivo tumorigenicity assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, kinase inhibitors, antibody shedding, shRNA KD, in vivo) establishing specific transphosphorylation mechanism\",\n      \"pmids\": [\"21212418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mutant Met receptors bearing kinase-activating mutations (unlike wild-type) circumvent ubiquitin-dependent lysosomal degradation and instead recycle to the plasma membrane via GGA3 adaptor protein recruitment. This recycling is mediated through GGA3 interaction with activated Arf6 and indirect binding to phosphorylated Met through adaptor protein Crk. Mutant receptors elicit enhanced signaling from endosomes critical for cell motility and tumorigenesis.\",\n      \"method\": \"Endocytic trafficking analysis, receptor recycling assays, adaptor protein interaction studies\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review/perspective synthesizing new mechanistic data on endosomal recycling pathway; GGA3/Arf6/Crk pathway supported by experimental data cited\",\n      \"pmids\": [\"21917713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structures of Met in complex with L. monocytogenes InlB suggest that Met dimerization is mediated by a dimer contact of the ligand. Structural comparison with HGF/SF reveals parallels and differences in Met activation mechanisms.\",\n      \"method\": \"X-ray crystallography of Met-InlB complex, structural comparison\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure established with bacterial ligand; mechanistic parallels to physiological HGF/SF activation are inferred by structural comparison, not directly demonstrated\",\n      \"pmids\": [\"21242015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PAX3 and ETS1 directly interact and synergistically activate MET expression through the 300 bp 5' proximal MET promoter, which contains a PAX3 response element and two ETS1 consensus motifs. ETS1 activates MET via PAX3-dependent and PAX3-independent mechanisms. HGF-dependent ETS1 activation enhances MET expression indirectly, creating a positive feedback loop. Dominant-negative ETS1 reduces melanoma cell growth in culture and in vivo.\",\n      \"method\": \"Promoter reporter assays, co-immunoprecipitation of PAX3-ETS1 interaction, ChIP, siRNA knockdown, dominant-negative constructs, in vivo tumor growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein-protein interaction demonstrated by Co-IP, promoter mechanism established by multiple binding site analyses, in vivo functional validation\",\n      \"pmids\": [\"25531327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Somatic splice site alterations at MET exon 14 (METex14) result in exon skipping, loss of the juxtamembrane domain (which contains a negative regulatory region and the Cbl E3 ligase binding site Y1003), and constitutive MET kinase activation leading to oncogenic transformation in vitro. Cells harboring METex14 alterations are sensitive to MET inhibitors.\",\n      \"method\": \"Comprehensive genomic profiling of 38,028 tumor samples, functional in vitro studies of METex14 alterations, MET inhibitor sensitivity assays\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanism of activation (loss of juxtamembrane regulatory domain) established with functional in vitro validation across large patient cohort; multiple labs have replicated clinical findings\",\n      \"pmids\": [\"25971938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MET kinase domain fusions (TRIM4-MET and ZKSCAN1-MET) constitutively activate MAPK, PI3K, and PLCγ1 signaling pathways. These fusion kinases are blocked by MET inhibitors cabozantinib and PF-04217903 at nanomolar concentrations.\",\n      \"method\": \"Identification of MET fusions by genomic analysis, functional characterization of fusion proteins with western blotting for downstream signaling, MET inhibitor treatment assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional characterization of two fusion proteins with signaling pathway analysis and inhibitor sensitivity; single study\",\n      \"pmids\": [\"26013381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A missense mutation c.2521T>G (p.F841V) in MET (encoding the hepatocyte growth factor receptor) is associated with autosomal recessive non-syndromic hearing loss (DFNB97) in humans, mapped to chromosome 7q31.2, establishing MET function in auditory system development.\",\n      \"method\": \"Homozygosity mapping with 1 million SNP array, whole-exome sequencing, Sanger confirmation, cosegregation analysis, absence from 800 control chromosomes\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic linkage and exome sequencing identify causal mutation; functional validation is indirect (prediction programs) without in vitro mechanistic follow-up\",\n      \"pmids\": [\"25941349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRZ1-MET (ZM) fusion proteins preserve fundamental properties of wild-type MET with respect to processing and dimerization, and enhance MET phosphorylation in both HGF-dependent and HGF-independent manners. ZM fusions increase MET mRNA expression levels.\",\n      \"method\": \"Western blotting, phosphorylation analysis, dimerization assays, mRNA expression analysis in ZM fusion-carrying patient samples and cell models\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization of fusion protein properties including HGF-independent activation; single lab\",\n      \"pmids\": [\"25935522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MET signaling in keratinocytes activates EGFR through autocrine EGFR ligand synthesis and release, mediated by the kinase SRC, the pseudoproteases iRhom1 and iRhom2, and the metallopeptidase ADAM17. Pharmacological EGFR inhibition caused regression of MET-driven spontaneous squamous tumors.\",\n      \"method\": \"Transgenic MT-HGF mouse model, keratinocyte culture studies, Western blotting for signaling, pharmacological inhibition of EGFR/SRC/ADAM17, gene expression profiling\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanism established in both in vitro keratinocyte models and in vivo transgenic tumor models with pharmacological rescue experiments; multiple pathway components identified\",\n      \"pmids\": [\"27330189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In MET-amplified cancer cells, MET inhibition counteracts IFN-γ-induced PD-L1/PD-L2 upregulation. JAK2 and MET physically associate in the same signaling complex in a MET phosphorylation-dependent manner. MET inhibitors (JNJ-605, MvDN30) neutralize JAK/STAT1 signaling downstream of the IFN-γ receptor, preventing PD-1 ligand induction.\",\n      \"method\": \"Co-immunoprecipitation of MET-JAK2 complex, PD-L1/PD-L2 expression analysis, MET inhibitor treatment, signaling pathway analysis in MET-amplified cell lines and patient-derived tumor organoids\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing MET-JAK2 complex, validated in organoid models, multiple inhibitors and cell lines tested\",\n      \"pmids\": [\"30723303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"METex14 skipping results in loss of the juxtamembrane domain, retaining HGF affinity but eliminating negative regulatory function, leading to receptor accumulation on the cell surface and prolonged HGF-dependent activation.\",\n      \"method\": \"Review synthesizing functional studies of METex14 deletion consequences on receptor biology\",\n      \"journal\": \"Cancer treatment reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic interpretation supported by functional studies reported across multiple laboratories; single review paper but based on replicated experimental findings\",\n      \"pmids\": [\"32334240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ENO1 (alpha-enolase) directly interacts with MET (HGFR) and activates HGFR signaling via increased phosphorylation of HGFR. This interaction activates Wnt coreceptor LRP5/6, decreases GSK3β activity via Src-PI3K-AKT signaling, inactivates the β-catenin destruction complex, and upregulates SLUG and β-catenin to promote EMT and lung cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation of ENO1-HGFR, Western blotting for phosphorylation, knockdown/overexpression studies, in vivo orthotopic and tail-vein injection models, anti-ENO1 antibody treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP establishing ENO1-HGFR interaction, mechanistic pathway characterized with multiple downstream readouts, validated in vivo\",\n      \"pmids\": [\"34145039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MET-deficient neutrophils (MRP8-Cre MET-LoxP mice) show reduced severity of DSS-induced colitis, decreased TH17 cell numbers, and decreased IL-1β production, establishing that neutrophilic HGF-MET signaling promotes intestinal inflammation through IL-1β-mediated TH17 expansion.\",\n      \"method\": \"Conditional knockout mice (MRP8-Cre MET-LoxP), DSS colitis model, flow cytometry for immune cell populations, cytokine quantification\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockout with well-defined phenotypic and mechanistic readouts establishing MET function in neutrophil-mediated inflammation\",\n      \"pmids\": [\"32556102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CYP1A2 suppresses HGF/MET signaling by binding to HIF-1α (transcriptional activator of MET) and inducing ubiquitin-mediated degradation of HIF-1α, thereby inhibiting HIF-1α-mediated MET transcription. CYP1A2 also decreases HGF levels, reducing MET activation.\",\n      \"method\": \"Co-immunoprecipitation of CYP1A2-HIF-1α interaction, ubiquitination assays, Western blotting, CYP1A2 overexpression/knockdown studies, in vivo tumor model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes binding, ubiquitination assay establishes degradation mechanism; single lab study\",\n      \"pmids\": [\"33500715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Circular MET RNA (circMET) encodes a 404-amino-acid MET variant (MET404) whose translation is facilitated by the m6A reader YTHDF2. MET404 directly interacts with the MET beta subunit forming a constitutively activated MET receptor complex whose activity does not require HGF stimulation. Genetic ablation of circMET in mice attenuates MET signaling; MET404 knock-in plus P53 knockout in mouse astrocytes initiates GBM tumorigenesis.\",\n      \"method\": \"circMET genetic ablation in mice, MET404 knock-in mouse model, co-immunoprecipitation of MET404-MET beta subunit, neutralizing antibody treatment, in vitro and in vivo tumorigenicity assays, YTHDF2 functional studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including in vivo genetic models (KI/KO), direct protein-protein interaction by Co-IP, neutralizing antibody validation, and mechanistic characterization of HGF-independent activation\",\n      \"pmids\": [\"37491377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EpCAM extracellular domain (EpEX) physically binds to MET (HGFR) and activates downstream ERK and FAK-AKT signaling, stabilizes active β-catenin and Snail proteins via GSK3β inactivation, and promotes EMT and metastatic potential. EpEX and HGF cooperatively mediate HGFR signaling.\",\n      \"method\": \"Co-immunoprecipitation, ELISA, FRET analysis of EpEX-HGFR interaction, Western blotting for downstream signaling, in vivo metastasis models (tail vein injection and orthotopic)\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three orthogonal methods (Co-IP, ELISA, FRET) establishing direct EpEX-HGFR interaction, mechanistic pathway characterized with in vivo validation\",\n      \"pmids\": [\"37543570\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MET encodes a heterodimeric (alpha-beta) receptor tyrosine kinase for HGF/SF; upon ligand binding or oncogenic activation (chromosomal translocation generating Tpr-Met, gene amplification, exon 14 skipping losing the juxtamembrane Cbl-binding negative regulatory domain, or kinase domain fusions), MET autophosphorylates and recruits a multi-substrate docking complex (Gab1, Grb2, SHP2, STAT3, Shc, Src, PI3K) to activate MAPK/ERK, PI3K/AKT, and PLCγ1 pathways driving proliferation, motility, invasion, and tubulogenesis; MET is downregulated via Cbl E3-ligase-mediated ubiquitination and lysosomal degradation, a process circumvented by activating mutations that redirect the receptor to endosomal recycling; MET transcription is driven by Ets1/PAX3/SOX10 transcription factors and negatively post-transcriptionally regulated by miR-34b/c and miR-199a*; MET also forms signaling complexes with JAK2, EGFR, and Ron, transphosphorylating Ron in MET-addicted cells and transactivating EGFR via SRC/iRhom/ADAM17-mediated ligand shedding, while a circRNA-encoded MET variant (MET404) constitutively activates MET signaling independent of HGF.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MET encodes a heterodimeric (α-β) receptor tyrosine kinase whose activation drives proliferation, motility, invasion, and epithelial tubulogenesis, and which is a recurrent oncogenic driver across multiple cancers [#1, #4]. Originally identified through a carcinogen-induced chromosomal translocation fusing the TPR locus to MET to generate the constitutively active Tpr-Met oncogene [#0], the receptor is a p190 complex of a 50 kDa α chain disulfide-linked to a 145 kDa β chain with intrinsic tyrosine kinase activity that is amplified and constitutively phosphorylated in tumor cells [#1]. Upon activation MET autophosphorylates and uses its C-terminal multisubstrate docking site to recruit Grb2, Gab1, SHP2, STAT3, Shc, SHIP-1, and Src, engaging PI3K, PLCγ, Src, and the ERK/MAP kinase cascade to sustain morphogenesis and survival signaling [#2, #4, #6]. Receptor output is normally limited by Cbl-mediated ubiquitination and lysosomal degradation; oncogenic activation circumvents this control, with exon 14 skipping deleting the juxtamembrane Cbl-binding negative regulatory domain to prolong signaling, and kinase-activating mutants redirected to GGA3-dependent endosomal recycling that enhances signaling [#5, #11, #14, #20]. Diverse oncogenic activation modes converge on this kinase, including MET amplification, METex14 skipping, kinase-domain fusions (TRIM4-MET, ZKSCAN1-MET, PTPRZ1-MET) that constitutively fire MAPK/PI3K/PLCγ1, and a circRNA-encoded MET404 variant that binds the MET β subunit to assemble an HGF-independent active receptor [#14, #15, #17, #24]. MET transcription is driven by Ets1, PAX3, and SOX10 through the proximal promoter, and is restrained post-transcriptionally by miR-34b/c and miR-199a* [#3, #7, #9, #13]. The receptor cross-talks with other signaling systems, transphosphorylating Ron in MET-addicted cells, complexing with JAK2 to control IFN-γ-induced PD-L1/PD-L2 induction, and transactivating EGFR via SRC/iRhom/ADAM17-mediated ligand shedding; binding partners ENO1 and EpCAM (EpEX) further amplify MET signaling toward β-catenin-driven EMT and metastasis [#10, #18, #19, #21, #25]. Beyond cancer, MET function extends to auditory development, where a missense mutation causes autosomal recessive non-syndromic hearing loss (DFNB97), and to neutrophil-driven intestinal inflammation through IL-1β-mediated TH17 expansion [#16, #22]. Acquired resistance to MET inhibitors arises through MET amplification and subsequent KRAS amplification that shifts cells to KRAS dependence [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Established that MET can be activated as an oncogene, defining the first mechanism by which a chromosomal rearrangement creates a constitutively active MET kinase.\",\n      \"evidence\": \"Southern blotting, chromosomal mapping, and NIH 3T3 transformation of carcinogen-treated HOS cells generating the Tpr-Met fusion\",\n      \"pmids\": [\"2423252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not characterize the normal receptor structure or ligand\", \"Frequency of TPR-MET in spontaneous human tumors not addressed\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Defined MET as a heterodimeric α-β receptor tyrosine kinase and linked gene amplification to constitutive kinase activity in tumor cells.\",\n      \"evidence\": \"Anti-phosphotyrosine IP, non-reducing SDS-PAGE, and amplification analysis in the GTL-16 gastric line\",\n      \"pmids\": [\"2541345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream substrates not yet mapped\", \"Ligand-dependent activation not characterized\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Mapped the immediate signaling output of HGF-activated MET, identifying the effectors that transduce the receptor's mitogenic and motogenic signals.\",\n      \"evidence\": \"In vitro kinase assays and phosphotyrosine IP showing rapid PI3K, GAP, PLCγ, Src, and MAPK engagement\",\n      \"pmids\": [\"8380734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs adaptor-mediated recruitment not resolved\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showed how MET expression is transcriptionally driven, identifying Ets1 as a promoter-binding activator in a positive feedback loop with MET signaling.\",\n      \"evidence\": \"MET promoter deletion, reporter co-transfection, stable Ets1 overexpression, and decoy oligonucleotides\",\n      \"pmids\": [\"8934537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue specificity of Ets1 control unclear\", \"Cooperating factors not yet defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected MET signaling to epithelial tubulogenesis through the Gab1/SHP2 module required for sustained ERK activation.\",\n      \"evidence\": \"Review synthesizing 3D branching morphogenesis assays and dominant-negative epistasis\",\n      \"pmids\": [\"12791299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis rather than single primary dataset\", \"Quantitative contribution of each effector to morphogenesis not parsed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established Cbl-mediated ubiquitination and lysosomal degradation as the negative control on MET, and linked its loss to transformation.\",\n      \"evidence\": \"Endocytic trafficking, ubiquitination assays, and Cbl-binding-defective mutant transformation assays\",\n      \"pmids\": [\"15645709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endosomal signaling output not quantified here\", \"Recycling fate of escapee receptors not yet defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the C-terminal multisubstrate docking site structurally and as the hub recruiting the adaptor/effector ensemble.\",\n      \"evidence\": \"Crystal structure of the MET kinase domain with domain-interaction analysis (review)\",\n      \"pmids\": [\"16132696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural source synthesized in a review\", \"Phosphosite-specific binding stoichiometry not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified post-transcriptional restraint of MET, showing specific miRNAs limit receptor levels and the invasive growth program.\",\n      \"evidence\": \"AntagomiR knockdown and miRNA overexpression with migration and signaling readouts in cancer/melanoma cells\",\n      \"pmids\": [\"19074879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous miRNA dosage in tumors not established\", \"Other 3'UTR regulators not surveyed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a clinically relevant resistance mechanism to MET inhibitors, showing oncogene switching from MET to KRAS.\",\n      \"evidence\": \"In vitro selection with two MET inhibitors across lines, copy-number and phosphorylation analysis\",\n      \"pmids\": [\"20841479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KRAS bypass occurs in patients not tested here\", \"Other bypass routes not enumerated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended transcriptional control of MET to the melanocyte lineage, defining PAX3/SOX10/MITF cooperation at the promoter.\",\n      \"evidence\": \"Promoter binding, reporter, co-transfection, and ChIP in melanoma cells\",\n      \"pmids\": [\"20067553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of direct vs MITF-indirect routes not quantified\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed how activating mutants evade degradation by GGA3/Arf6/Crk-mediated endosomal recycling, linking trafficking to oncogenic signaling.\",\n      \"evidence\": \"Endocytic trafficking and recycling assays with adaptor-interaction studies\",\n      \"pmids\": [\"21917713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synthesized as a perspective\", \"Endosomal signaling effectors not fully defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established MET-driven transphosphorylation of Ron as a functional cross-talk required for the malignant phenotype in MET-addicted cells.\",\n      \"evidence\": \"Co-IP, kinase inhibitors, antibody-induced shedding, RON shRNA, and in vivo tumorigenicity\",\n      \"pmids\": [\"21212418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of MET-Ron complex not defined\", \"Generality beyond MET-addicted lines unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided structural insight into MET dimerization via the bacterial ligand InlB, with inferred parallels to HGF/SF activation.\",\n      \"evidence\": \"X-ray crystallography of MET-InlB complex and structural comparison\",\n      \"pmids\": [\"21242015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Parallels to physiological HGF activation inferred, not directly shown\", \"HGF-bound dimer geometry not resolved here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed direct PAX3-ETS1 protein interaction and synergy at the proximal MET promoter, integrating two transcriptional inputs into a feedback loop with functional tumor relevance.\",\n      \"evidence\": \"Reporter assays, Co-IP, ChIP, siRNA, dominant-negative ETS1, and in vivo tumor growth\",\n      \"pmids\": [\"25531327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter architecture in non-melanoma contexts not tested\", \"Chromatin state dependence not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined METex14 skipping as a recurrent activating event that deletes the juxtamembrane Cbl-binding regulatory domain and confers inhibitor sensitivity.\",\n      \"evidence\": \"Genomic profiling of 38,028 tumors with functional in vitro transformation and inhibitor assays\",\n      \"pmids\": [\"25971938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative degradation defect not directly measured here\", \"Tissue-specific frequency drivers unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established MET kinase-domain fusions as constitutive activators of MAPK/PI3K/PLCγ1 amenable to MET inhibition.\",\n      \"evidence\": \"Genomic identification and functional signaling/inhibitor characterization of TRIM4-MET and ZKSCAN1-MET\",\n      \"pmids\": [\"26013381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"In vivo tumorigenicity of these fusions not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Characterized PTPRZ1-MET fusion processing and HGF-independent activation, broadening the fusion-driven activation repertoire.\",\n      \"evidence\": \"Western blotting, phosphorylation, dimerization, and mRNA analysis in ZM-carrying samples/models\",\n      \"pmids\": [\"25935522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab\", \"Downstream pathway selectivity not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked MET to a Mendelian phenotype, identifying a causal missense mutation in autosomal recessive non-syndromic hearing loss (DFNB97).\",\n      \"evidence\": \"Homozygosity mapping, whole-exome sequencing, Sanger confirmation, and cosegregation in a family\",\n      \"pmids\": [\"25941349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of p.F841V validated only by prediction\", \"Mechanism in auditory development not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined MET-to-EGFR transactivation via SRC/iRhom/ADAM17-mediated ligand shedding, revealing a therapeutically exploitable cross-talk in MET-driven tumors.\",\n      \"evidence\": \"MT-HGF transgenic mice, keratinocyte cultures, and pharmacological EGFR/SRC/ADAM17 inhibition with tumor regression\",\n      \"pmids\": [\"27330189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across epithelial tissues not established\", \"Relative weight of autocrine EGFR ligands not parsed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a physical MET-JAK2 complex controlling IFN-γ-induced PD-L1/PD-L2, linking MET to immune-evasion signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, MET inhibitors, and PD-ligand analysis in MET-amplified lines and patient-derived organoids\",\n      \"pmids\": [\"30723303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo immune consequences not directly tested\", \"Direct vs indirect MET-JAK2 contact unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ENO1 as a direct MET-activating partner driving Wnt/β-catenin-dependent EMT and metastasis.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, anti-ENO1 antibody, and in vivo orthotopic/tail-vein models\",\n      \"pmids\": [\"34145039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ENO1-MET binding unknown\", \"Generality beyond lung cancer untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a non-cancer in vivo role for MET in neutrophils, promoting intestinal inflammation through IL-1β-driven TH17 expansion.\",\n      \"evidence\": \"MRP8-Cre MET-LoxP conditional knockout in DSS colitis with flow cytometry and cytokine readouts\",\n      \"pmids\": [\"32556102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from MET to IL-1β not detailed\", \"Relevance to human IBD not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined CYP1A2 as an upstream suppressor of MET transcription by degrading HIF-1α, revealing a metabolic regulator of HGF/MET output.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, CYP1A2 gain/loss-of-function, and in vivo tumor model\",\n      \"pmids\": [\"33500715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab\", \"HIF-1α-independent effects on HGF not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that a circRNA-encoded MET404 variant assembles an HGF-independent active receptor, defining a non-canonical mode of constitutive MET activation in gliomagenesis.\",\n      \"evidence\": \"circMET ablation and MET404 knock-in mice, MET404-MET β Co-IP, neutralizing antibody, and tumorigenicity assays with YTHDF2 studies\",\n      \"pmids\": [\"37491377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency of MET404 across tumor types unknown\", \"Structural basis of MET404-β subunit activation not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified EpCAM ectodomain (EpEX) as a direct MET ligand-like partner cooperating with HGF to drive EMT and metastasis.\",\n      \"evidence\": \"Co-IP, ELISA, FRET, downstream signaling Westerns, and in vivo metastasis models\",\n      \"pmids\": [\"37543570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface not mapped\", \"Relative contribution of EpEX vs HGF in vivo not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse activation modes (amplification, METex14, fusions, MET404, non-HGF partners) differentially shape receptor trafficking, effector wiring, and therapeutic vulnerability remains incompletely resolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking each activation mode to downstream signaling bias\", \"Cross-talk hierarchy among Ron, EGFR, JAK2, ENO1, and EpCAM in vivo unestablished\", \"Predictive biomarkers for bypass resistance beyond KRAS not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 11, 20]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 14, 15, 24]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 9, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HGF\", \"GAB1\", \"SHP2\", \"GRB2\", \"RON\", \"JAK2\", \"ENO1\", \"EpCAM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}