{"gene":"HGF","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1993,"finding":"HGF is the ligand for p190MET (the receptor tyrosine kinase encoded by the MET proto-oncogene), proven by HGF binding to immunopurified p190MET, chemical cross-linking of radiolabelled ligand, HGF-induced tyrosine phosphorylation of p190MET, and reconstitution of high-affinity HGF binding sites in insect cells expressing human MET cDNA via baculovirus.","method":"Immunopurification binding assay, chemical cross-linking of radiolabelled ligand, tyrosine phosphorylation assay, baculovirus reconstitution in insect cells","journal":"EXS","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (binding, cross-linking, phosphorylation, reconstitution) in a single study; independently corroborated across the corpus","pmids":["8380735"],"is_preprint":false},{"year":1993,"finding":"HGF/SF and human Scatter Factor are identical proteins encoded by a single gene on chromosome 7q11.2-21. A single-chain HGF-SF with destroyed protease cleavage site (Arg494→Gln) is largely inactive, demonstrating that proteolytic cleavage is essential for biological activity. The separately expressed light chain (serine protease homology domain) is inactive, while the heavy chain and an N-terminal/two-kringle splice variant can bind MET, stimulate its tyrosine phosphorylation, and induce cell dissociation but not mitogenesis.","method":"Protein sequencing, cDNA analysis, immunological comparison, transient expression of mutagenized cDNAs, receptor tyrosine phosphorylation assay, biological activity assays","journal":"EXS","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis combined with functional assays and receptor activation readouts in a single focused study","pmids":["8380739"],"is_preprint":false},{"year":1993,"finding":"HGF receptor (p190MET) is a 190 kDa alpha-beta heterodimer of two disulfide-linked subunits derived from a 170 kDa precursor by glycosylation and proteolytic cleavage. The beta subunit contains the cytoplasmic tyrosine kinase domain; autophosphorylation at Tyr1235 upregulates kinase activity (increases Vmax). Negative regulation occurs via PKC activation or increased intracellular Ca2+, both leading to serine phosphorylation of the receptor and decreased kinase activity. The phosphorylated receptor associates Ras GAP, phospholipase C-gamma, src-related tyrosine kinase, and PI3-kinase in vitro.","method":"Biochemical receptor characterization, autophosphorylation mapping, mutagenesis, kinase activity assays, co-immunoprecipitation","journal":"EXS","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical characterization of receptor structure and enzymatic mechanism with phosphorylation site mapping and multiple effector associations","pmids":["8380735"],"is_preprint":false},{"year":1993,"finding":"HGF-induced branching morphogenesis of MDCK cells in collagen gels is modulated by multiple phosphorylation mechanisms: PKC inhibition enhances branching; PKA activators and calmodulin antagonists reduce it; protein phosphatase inhibition (okadaic acid, calyculin A) markedly inhibits branching; and tyrosine kinase inhibition decreases branching, consistent with MET TK activity being required.","method":"MDCK collagen gel tubulogenesis assay with pharmacological kinase/phosphatase modulators","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean cellular morphogenesis assay with multiple pharmacological interventions, single lab","pmids":["8405677"],"is_preprint":false},{"year":1995,"finding":"After HGF-induced tyrosine phosphorylation of MET, the Shc adaptor protein binds via its SH2 domain to phosphotyrosines Y1349VHV and Y1356VNV on the receptor (Kd ~150 nM for both sites, measured by BIAcore). Shc is then phosphorylated on Y317VNV, generating a high-affinity Grb2 binding site (Kd ~15 nM), thereby amplifying Ras pathway activation. Overexpression of wild-type Shc (but not Y317F mutant) enhances HGF-stimulated cell migration and growth.","method":"Site-directed mutagenesis of HGF receptor, BIAcore biosensor binding kinetics with synthetic phosphopeptides and recombinant Shc, co-immunoprecipitation, overexpression of Shc mutants, motility and proliferation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding kinetics plus site-directed mutagenesis plus functional rescue assays in a single rigorous study","pmids":["7731718"],"is_preprint":false},{"year":1997,"finding":"The MET receptor signals through a two-phosphotyrosine 'multifunctional docking site' that simultaneously binds and activates multiple SH2-containing transducers including Ras and PI3-kinase, a feature shared with the related RON and SEA receptors and distinct from conventional growth factor receptors.","method":"Signal transduction analysis, receptor mutagenesis, biochemical characterization of docking site","journal":"Cytokine & growth factor reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review synthesis of receptor biochemistry established by the same group; docking site mechanism confirmed by mutagenesis in referenced primary work","pmids":["9244408"],"is_preprint":false},{"year":1997,"finding":"Gab1 was identified as a direct-binding substrate of the c-Met receptor; Gab1 binds to c-Met phosphorylated on tyrosine residues via a proline-rich domain that interacts with the bidentate docking site. Expression of Gab1 in epithelial cells is sufficient to induce c-Met-specific branching tubulogenesis.","method":"Direct binding assay (immunoprecipitation), domain mapping, gain-of-function expression of Gab1 in epithelial cells with morphogenesis readout","journal":"Ciba Foundation symposium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and functional rescue experiments; single lab, abstract-level detail","pmids":["9524774"],"is_preprint":false},{"year":1997,"finding":"Met-HGF/SF autocrine signaling activates the urokinase plasminogen proteolysis network, coupling Met signal transduction to extracellular matrix dissolution and enabling invasiveness and branching morphogenesis.","method":"Cell line models with autocrine Met-HGF/SF expression, in vitro invasiveness assays, biochemical pathway analysis","journal":"Ciba Foundation symposium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional demonstration in defined cell models with biochemical pathway linkage; single lab, abstract level","pmids":["9524767"],"is_preprint":false},{"year":1999,"finding":"The single-chain HGF precursor is cleaved by specific serine proteases at the Arg494-Val495 bond to generate the biologically active alpha-beta heterodimer. HGF activator (HGFA), a coagulation factor XII-like serine proteinase, is critically involved in pericellular HGF activation; its activity is regulated by Kunitz-type transmembrane inhibitors HAI-1 and HAI-2, which also inhibit matriptase, plasmin, trypsin, and kallikreins.","method":"Biochemical identification of cleavage site, characterization of HGFA serine proteinase activity, identification and functional characterization of HAI-1 and HAI-2 inhibitors","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical cleavage site mapping and in vitro proteinase/inhibitor characterization; replicated across multiple studies in the corpus","pmids":["10641789","12784998"],"is_preprint":false},{"year":2003,"finding":"NK4 (comprising the N-terminal domain and four kringle domains of HGF) competitively antagonizes HGF binding to c-Met without activating it, blocking all HGF biological activities. NK4 also inhibits angiogenesis induced by VEGF and bFGF independently of its HGF-antagonist action, establishing it as a bifunctional molecule.","method":"Competitive receptor binding assay, biological activity assays (cell proliferation, scattering, invasion), in vivo angiogenesis models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive binding demonstrated with functional activity assays; angiogenesis inhibition confirmed in vivo; single lab","pmids":["12824898"],"is_preprint":false},{"year":2003,"finding":"EphA kinase activation by ephrin-A1 negatively regulates HGF-induced branching morphogenesis in MDCK cells by inhibiting HGF-induced activation of Rac1 and PAK while retaining RhoA activation, leading to preservation of stress fibers. Dominant-negative RhoA or ROCK inhibitor (Y27632) reversed the ephrin-A1 inhibitory effect, placing Rho GTPase signaling downstream of both HGF/Met and EphA.","method":"Collagen gel branching morphogenesis assay, Rac1/RhoA GTPase pull-down assays, dominant-negative constructs, pharmacological ROCK inhibitor, live cell imaging of protrusion dynamics","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal genetic and pharmacological tools with GTPase biochemistry; rigorous epistasis established","pmids":["14517207"],"is_preprint":false},{"year":2004,"finding":"PKCepsilon controls HGF/c-Met signaling to the ERK cascade specifically within endosomal compartments, causing ERK accumulation in focal complexes. PKCalpha controls subsequent microtubule-dependent sorting of c-Met to a perinuclear destination. Endosomal traffic is essential for HGF/c-Met to trigger an ERK response, and PKCepsilon-dependent dynamic properties of this endosomal signaling are required for normal HGF-dependent cell migration.","method":"Live cell imaging, subcellular fractionation, pharmacological and dominant-negative PKC isotype manipulation, ERK localization by immunofluorescence, migration assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct localization experiments tied to signaling and functional consequences, with isotype-specific PKC dissection; multiple orthogonal methods","pmids":["15385963"],"is_preprint":false},{"year":2004,"finding":"HGF disrupts ErbB2/NeuNT-induced epithelial morphogenesis in MDCK cells, stimulating breakdown of cell-cell junctions (loss of claudin-1 and E-cadherin, internalization of ZO-1) and promoting single-cell invasion. This process requires MEK-dependent signaling downstream of HGF/Met, as MEK inhibition restores junctional E-cadherin and ZO-1 and abrogates HGF-induced invasion.","method":"3D MDCK collagen culture invasion assay, MEK pharmacological inhibitor, immunofluorescence of junctional proteins, cell biology readouts","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional invasion assay with pharmacological pathway dissection and molecular marker readouts; single lab","pmids":["15548598"],"is_preprint":false},{"year":2006,"finding":"HGF induces CXCR4 expression and CXCL12-dependent invasion in MCF-7 breast cancer cells through the MAPK1/ERK1/2 pathway activating Ets1 transcription factor, and through NF-kappaB. Dominant-negative constructs and inhibitors of Ets1 and NF-kappaB block HGF-induced CXCR4 transcription and chemoinvasion.","method":"Reporter gene assay (CXCR4 promoter luciferase), dominant-negative transcription factor constructs, pharmacological inhibitors, EMSA/DNA binding assays, chemoinvasion assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus dominant-negative constructs plus inhibitors; single lab","pmids":["16840440"],"is_preprint":false},{"year":2008,"finding":"In prostate cancer cells, PAK4 binds to and phosphorylates LIMK1 in an HGF-dependent manner. PAK4 expression levels regulate cofilin phosphorylation (via LIMK1 activity), and PAK4 and LIMK1 interact at the cell periphery (demonstrated by FRET:FLIM). HGF-stimulated cell migration requires a cofilin phosphorylation step mediated by PAK4.","method":"Co-immunoprecipitation, in vitro kinase assay (PAK4 phosphorylation of LIMK1), FRET:FLIM for protein-protein interaction in live cells, siRNA knockdown, cofilin phosphorylation western blot, migration assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay plus FRET:FLIM plus functional migration assay; multiple orthogonal methods in a single study","pmids":["18424072"],"is_preprint":false},{"year":2009,"finding":"PAK1 and PAK2 have distinct roles downstream of HGF: PAK1 knockdown inhibits HGF-stimulated migration and loss of cell-cell junctions, whereas PAK2 knockdown enhances junction loss and lamellipodia extension without affecting migration speed. PAK2 provides negative feedback on PAK1 phosphorylation.","method":"siRNA knockdown of PAK1/PAK2, HGF-stimulated migration assay, immunofluorescence of cell-cell junctions, phosphorylation western blot","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific siRNA knockdown with multiple phenotypic readouts; single lab","pmids":["19628037"],"is_preprint":false},{"year":2009,"finding":"Noncoding mutations in HGF (two intronic deletions in a highly conserved sequence that is part of the 3'UTR of a short HGF isoform, and a silent exon 5 substitution affecting splicing) cause autosomal-recessive nonsyndromic hearing loss DFNB39. Mouse models of Hgf overexpression cause progressive outer hair cell degeneration; cochlear-specific Hgf conditional knockout causes general cochlear dysplasia.","method":"Sequencing of DFNB39 locus, in vitro splicing assay, mouse transgenic overexpression and conditional knockout models with auditory phenotyping","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetic mapping plus functional splicing assay plus two independent mouse models with defined cochlear phenotypes","pmids":["19576567"],"is_preprint":false},{"year":2013,"finding":"HGF-MET signaling results in accumulation of ETS2, which interacts with MLL to form a complex that transactivates MMP1 and MMP3. ChIP assays showed that HGF-MET pathway activation increases occupancy of the MLL-ETS2 complex on MMP1/MMP3 promoters and MLL-mediated H3K4 trimethylation, activating transcription. This epigenetic mechanism is required for HGF-induced hepatocellular carcinoma invasion and metastatic growth.","method":"Co-immunoprecipitation (MLL-ETS2 interaction), ChIP assay (promoter occupancy and H3K4me3), loss-of-function (MLL knockout cells/mice), invasion and metastasis assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal co-IP, ChIP, and genetic (Mll-/- mice) validation of epigenetic mechanism downstream of HGF-MET; multiple orthogonal methods","pmids":["23934123"],"is_preprint":false},{"year":2014,"finding":"HGF-induced resistance to MET kinase inhibitors in MET-amplified tumors is mediated by restoration of physiologic GAB1-mediated PI3K activation that compensates for loss of aberrant HER3-dependent PI3K signaling. HGF neutralization (ficlatuzumab) restores sensitivity to MET-targeted agents both in co-culture systems and in human HGF knock-in mice bearing MET-amplified tumors.","method":"Cell-based drug sensitivity assays +/- HGF, stroma-tumor co-culture system, human HGF knock-in mouse xenograft model, phosphoprotein signaling analysis (GAB1/PI3K/HER3), neutralizing antibody experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanism dissected in multiple complementary models (in vitro, co-culture, in vivo knock-in mouse) with defined signaling mechanism","pmids":["25217525"],"is_preprint":false},{"year":2015,"finding":"Arf6 is required for HGF-induced beta1 integrin recycling in endothelial cells and for HGF-dependent tumor neoangiogenesis and growth. Endothelial-specific Arf6 deletion abolishes HGF-stimulated beta1 integrin recycling. The Arf6 GEF Grp1 (as well as GEP100, EFA6B, EFA6D) regulates HGF-stimulated beta1 integrin recycling and can be pharmacologically inhibited to suppress tumor vascularization.","method":"Endothelial cell-targeted conditional knockout mice, beta1 integrin recycling assay, pharmacological Arf6 GEF inhibition, in vivo tumor angiogenesis and growth models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (conditional KO) plus pharmacological inhibition plus mechanistic recycling assay in vivo and in vitro; multiple orthogonal approaches","pmids":["26239146"],"is_preprint":false},{"year":2019,"finding":"HGF activates MET kinase, which phosphorylates the pyruvate dehydrogenase complex (PDHC) to inhibit its activity and phosphorylates GLS/GLS1 (glutaminase) to activate it, promoting the Warburg effect and glutaminolysis for cancer cell biogenesis. The key kinase activation residues Y1234/Y1235 in MET also constitute an LC3-interacting region (LIR) motif (Y1234-Y1235-x-V1237); when dephosphorylated (upon MET kinase inhibition), MET induces autophagy via this LIR motif to maintain biogenesis, representing an escape mechanism.","method":"In vitro kinase assay (MET phosphorylation of PDHC and GLS), metabolic flux analysis, LC3-interacting region mapping, autophagy assays, MET Y1234/1235 mutagenesis, in vitro and in vivo liver cancer models","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay identifying PDHC and GLS as MET substrates, LIR motif mapping, mutagenesis, and in vivo validation; multiple orthogonal methods","pmids":["30786811"],"is_preprint":false},{"year":2019,"finding":"MAP1LC3C (LC3C) selectively mediates autophagic degradation of the Met receptor via direct complex formation between Met and LC3C. LC3C deletion abrogates Met entry into the autophagy-dependent degradative pathway, resulting in enhanced Met stability, signaling, and cell invasion. This establishes a distinct role for LC3C among ATG8 family members in Met RTK downregulation.","method":"LC3C knockout (CRISPR), co-immunoprecipitation (Met-LC3C complex), domain mapping (LC3C domains required for rescue), Met stability and degradation assays, invasion assays in cancer cells with low LC3C","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO plus reciprocal co-IP plus domain rescue experiments plus functional invasion readout; multiple orthogonal methods","pmids":["31851933"],"is_preprint":false},{"year":2020,"finding":"In the inner ear, HGF is required for neural crest cell migration into the stria vascularis intermediate layer during development. A 10-bp noncoding intronic deletion (del10) in Hgf reduces cochlear HGF levels, causing failure of neural crest infiltration into the stria vascularis, reduced endocochlear potential, and consequent moderate-to-profound hearing loss recapitulating human DFNB39 deafness.","method":"Mouse model with engineered noncoding Hgf deletion, auditory brainstem response (tone burst ABR), endocochlear potential measurement, immunohistochemistry for neural crest cell migration in stria vascularis, RNAseq","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetically engineered mouse model with direct physiological (EP measurement) and cellular (IHC neural crest migration) mechanistic readouts; independent replication of DFNB39 findings","pmids":["32152201"],"is_preprint":false},{"year":2001,"finding":"HGF activates PI3-kinase and its downstream target p70 S6 kinase in corneal epithelial cells. PKC is involved in the PI3K-dependent (but not MAPK-dependent) activation of p70 S6K. Inhibition of PI3K (wortmannin) or p70 S6K (rapamycin) blocks HGF-promoted corneal epithelial wound healing in organ culture.","method":"PI3K activity assay, p70 S6K immunoprecipitation kinase assay, pharmacological inhibitors (wortmannin, rapamycin, calphostin C, PD98059), corneal epithelial wound healing organ culture model","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase activity assays with pharmacological dissection and functional wound healing readout; single lab","pmids":["11446769"],"is_preprint":false},{"year":2002,"finding":"HGF induces MAP kinase-dependent ARPE-19 cell migration accompanied by tyrosine phosphorylation of both the HGF receptor (c-met) and beta-catenin, increased cytosolic levels of beta-catenin, and transactivation activity of beta-catenin. Both beta-catenin and MAP kinases are components of the HGF-induced RPE migration pathway.","method":"Quantitative migration assay, immunoprecipitation/western blot for HGF receptor and beta-catenin phosphorylation, beta-catenin luciferase reporter (transactivation), MEK inhibitor (MAP kinase pathway inhibition), immunofluorescence","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assays plus reporter assay plus pharmacological dissection; single lab","pmids":["12500177"],"is_preprint":false},{"year":2022,"finding":"HGF activates c-MET-ERK1/2-ELK1 signaling to upregulate ETV1 expression, which in turn transcriptionally activates PTK2 (FAK) and MET itself, creating a positive feedback loop. ETV1 ChIP occupancy on PTK2 and MET promoters was demonstrated, and inhibiting PTK2 or c-MET downstream of ETV1 decreased ETV1-mediated HCC metastasis.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP) for ETV1 on PTK2 and MET promoters, western blot for signaling intermediates, transwell invasion assay, orthotopic metastatic mouse model, siRNA knockdown","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus in vivo model; single lab, abstract-level detail","pmids":["36109787"],"is_preprint":false}],"current_model":"HGF is a mesenchymally secreted, proteolytically activated (at Arg494-Val495 by serine proteases including HGFA) alpha-beta heterodimeric ligand that binds and activates the MET receptor tyrosine kinase, triggering autophosphorylation at Tyr1235 (among other sites) and recruitment of multiple SH2-domain effectors (including Shc→Grb2/Ras, PI3K, Gab1, PLC-gamma) through a bidentate multifunctional docking site; activated MET signals through endosomal compartments (regulated by PKCepsilon/PKCalpha), controls Rho GTPases (Rac1, Cdc42, RhoA) and downstream kinases (PAK1, PAK2, PAK4-LIMK1-cofilin) to drive cell proliferation, migration, scattering, and branching morphogenesis; phosphorylates metabolic enzymes PDHC (inhibiting) and GLS (activating) to reprogram cancer metabolism; engages an MLL-ETS2 epigenetic complex to activate MMP transcription; is degraded via LC3C-mediated selective autophagy; and in the inner ear signals through MET to direct neural crest cell migration into the stria vascularis, with fine-tuned HGF levels being essential for normal hearing."},"narrative":{"mechanistic_narrative":"HGF is a mesenchymally derived secreted ligand that controls epithelial proliferation, migration, scattering, and branching morphogenesis by binding and activating the MET receptor tyrosine kinase (p190MET) [PMID:8380735]. HGF is synthesized as an inactive single-chain precursor that must be proteolytically cleaved at the Arg494-Val495 bond to form the active disulfide-linked alpha-beta heterodimer; a cleavage-site mutant is largely inactive, and pericellular activation is carried out by serine proteases such as HGF activator (HGFA), which is itself restrained by the Kunitz-type inhibitors HAI-1 and HAI-2 [PMID:8380739, PMID:10641789, PMID:12784998]. Ligand binding drives MET autophosphorylation at Tyr1235 and assembles a bidentate two-phosphotyrosine docking site that simultaneously recruits multiple SH2-domain effectors, including Shc (which amplifies Ras/Grb2 signaling), PI3-kinase, PLC-gamma, and Gab1, the latter being sufficient to drive MET-specific branching tubulogenesis [PMID:8380735, PMID:7731718, PMID:9244408, PMID:9524774]. Downstream, HGF/MET signaling routes through endosomal compartments under PKCepsilon/PKCalpha control to sustain ERK responses required for migration, and engages Rho-family GTPases (Rac1, RhoA) and the PAK4-LIMK1-cofilin axis to remodel the cytoskeleton, dissolve cell-cell junctions, and promote invasion [PMID:15385963, PMID:14517207, PMID:18424072, PMID:15548598]. HGF/MET drives invasive and metastatic programs through transcriptional and epigenetic outputs, activating the urokinase proteolysis network, inducing CXCR4 and ETV1-dependent feedback loops, and assembling an MLL-ETS2 complex that deposits H3K4me3 to transactivate MMP1/MMP3 [PMID:9524767, PMID:16840440, PMID:23934123, PMID:36109787]. MET also reprograms cancer metabolism by phosphorylating and inhibiting the pyruvate dehydrogenase complex while activating glutaminase, and is itself downregulated by LC3C-mediated selective autophagy [PMID:30786811, PMID:31851933]. In development, fine-tuned cochlear HGF levels are required for neural crest migration into the stria vascularis; noncoding HGF mutations that perturb these levels cause autosomal-recessive nonsyndromic hearing loss DFNB39 [PMID:19576567, PMID:32152201].","teleology":[{"year":1993,"claim":"Establishing that HGF is the physiological ligand for the MET proto-oncogene product defined the entire downstream signaling system and linked a secreted growth factor to an oncogenic receptor.","evidence":"Binding, chemical cross-linking, receptor phosphorylation, and baculovirus reconstitution of MET in insect cells","pmids":["8380735"],"confidence":"High","gaps":["Stoichiometry of the active HGF-MET complex not resolved here","Structural basis of high-affinity binding not defined"]},{"year":1993,"claim":"Demonstrating that proteolytic cleavage at Arg494-Val495 converts inactive single-chain HGF into the active heterodimer answered how HGF activity is post-translationally gated, and dissected which chains carry binding versus mitogenic function.","evidence":"Protein sequencing, mutagenesis of the cleavage site, and functional/receptor-activation assays on separated chains","pmids":["8380739"],"confidence":"High","gaps":["Identity of the activating protease not yet established","Mechanism by which the heavy chain alone activates MET but not mitogenesis unclear"]},{"year":1993,"claim":"Biochemical characterization of MET as an alpha-beta heterodimer with Tyr1235 autophosphorylation upregulating kinase activity, plus negative regulation via PKC/Ca2+ serine phosphorylation, established the receptor's catalytic mechanism and its in vitro effector associations.","evidence":"Receptor characterization, autophosphorylation mapping, kinase assays, and co-immunoprecipitation of RasGAP, PLC-gamma, Src, PI3K","pmids":["8380735"],"confidence":"High","gaps":["In vitro associations not yet validated as functional in cells","Hierarchy of effector recruitment undefined"]},{"year":1995,"claim":"Quantifying Shc binding to MET phosphotyrosines Y1349/Y1356 and the Shc-Y317-generated Grb2 site clarified how HGF amplifies Ras pathway output and links receptor docking to migration and growth.","evidence":"BIAcore phosphopeptide kinetics, receptor and Shc mutagenesis, co-IP, and motility/proliferation rescue assays","pmids":["7731718"],"confidence":"High","gaps":["Relative contribution of Shc versus other docking effectors not quantified","Downstream Ras effector specificity not addressed"]},{"year":1997,"claim":"Defining the two-phosphotyrosine 'multifunctional docking site' and identifying Gab1 as a direct binder sufficient to drive branching tubulogenesis explained how a single receptor coordinates multiple transducers for morphogenesis.","evidence":"Docking-site mutagenesis, direct binding/domain mapping, and gain-of-function Gab1 expression with morphogenesis readout","pmids":["9244408","9524774"],"confidence":"Medium","gaps":["Gab1 findings at abstract-level detail from a single lab","Whether Gab1 recruitment is direct or PI3K/Grb2-bridged not fully resolved"]},{"year":1997,"claim":"Linking autocrine Met-HGF signaling to the urokinase plasminogen network coupled receptor activation to extracellular matrix dissolution, providing a mechanism for invasiveness.","evidence":"Autocrine cell-line models with invasiveness assays and biochemical pathway analysis","pmids":["9524767"],"confidence":"Medium","gaps":["Direct transcriptional targets within the uPA network not identified here","Single-lab, abstract-level detail"]},{"year":1999,"claim":"Identifying HGFA as the critical pericellular activating serine protease and HAI-1/HAI-2 as its inhibitors mapped the proteolytic control circuit that governs where and when HGF is activated.","evidence":"Cleavage-site mapping, HGFA proteinase characterization, and functional analysis of HAI-1/HAI-2 inhibitors","pmids":["10641789","12784998"],"confidence":"High","gaps":["Relative in vivo contribution of HGFA versus other proteases unquantified","Spatial regulation of inhibitor activity not resolved"]},{"year":2001,"claim":"Showing HGF activates PI3K and p70 S6K to drive corneal epithelial wound healing extended MET signaling to a regenerative, translational-control output and placed PKC upstream of the PI3K-dependent arm.","evidence":"PI3K and p70 S6K kinase assays with wortmannin/rapamycin/PKC inhibitors in a corneal wound-healing organ culture","pmids":["11446769"],"confidence":"Medium","gaps":["Direct PI3K-to-S6K linkage inferred pharmacologically","Single-lab tissue model"]},{"year":2002,"claim":"Demonstrating HGF-induced beta-catenin tyrosine phosphorylation and transactivation in RPE cells linked MET signaling to a transcriptional effector during migration.","evidence":"Migration assay, phospho-IP/western blot, beta-catenin luciferase reporter, and MEK inhibition","pmids":["12500177"],"confidence":"Medium","gaps":["Direct beta-catenin target genes not identified","Single-lab cell model"]},{"year":2003,"claim":"Mapping EphA/ephrin-A1 antagonism of HGF branching onto Rac1/PAK suppression with retained RhoA defined how counter-signals balance the cytoskeletal output of MET.","evidence":"Branching morphogenesis assays, GTPase pull-downs, dominant-negative RhoA, and ROCK inhibitor epistasis","pmids":["14517207"],"confidence":"High","gaps":["Molecular node where EphA intersects HGF signaling not pinpointed","In vivo relevance of the cross-talk untested"]},{"year":2003,"claim":"Characterizing NK4 as a competitive MET antagonist that also independently blocks angiogenesis established a bifunctional inhibitory tool and reinforced the receptor-binding map.","evidence":"Competitive binding, biological activity assays, and in vivo angiogenesis models","pmids":["12824898"],"confidence":"Medium","gaps":["Receptor/target mediating the HGF-independent anti-angiogenic effect undefined","Single-lab characterization"]},{"year":2004,"claim":"Showing that HGF/MET requires PKCepsilon/PKCalpha-controlled endosomal trafficking to generate localized ERK signaling reframed MET output as spatially compartmentalized and essential for migration.","evidence":"Live imaging, subcellular fractionation, isotype-specific PKC manipulation, and migration assays","pmids":["15385963"],"confidence":"High","gaps":["Endosomal sorting machinery beyond PKC isotypes not defined","Connection to specific migration effectors not mapped"]},{"year":2004,"claim":"Demonstrating that HGF overrides ErbB2-driven morphogenesis by dissolving junctions through MEK-dependent signaling explained how MET converts coherent epithelia into single-cell invaders.","evidence":"3D MDCK invasion assay with MEK inhibition and junctional-protein immunofluorescence","pmids":["15548598"],"confidence":"Medium","gaps":["Direct MEK targets at junctions not identified","Single-lab cell model"]},{"year":2006,"claim":"Linking HGF to ERK-Ets1 and NF-kappaB transcriptional induction of CXCR4 connected MET activation to chemokine-driven invasion programs.","evidence":"CXCR4 promoter reporter, dominant-negative Ets1/NF-kappaB, EMSA, and chemoinvasion assays","pmids":["16840440"],"confidence":"Medium","gaps":["Direct promoter occupancy versus indirect effects not fully resolved","Single-lab cell model"]},{"year":2008,"claim":"Establishing the HGF-dependent PAK4-LIMK1-cofilin phosphorylation cascade at the cell periphery defined a concrete cytoskeletal mechanism for MET-driven migration.","evidence":"Co-IP, in vitro PAK4 kinase assay on LIMK1, FRET:FLIM, siRNA, and migration assays","pmids":["18424072"],"confidence":"High","gaps":["Upstream link from MET to PAK4 activation not detailed","In vivo relevance untested"]},{"year":2009,"claim":"Dissecting opposing PAK1 versus PAK2 roles downstream of HGF revealed antagonistic regulation of migration and junction stability, with PAK2 providing negative feedback on PAK1.","evidence":"PAK1/PAK2 siRNA knockdown with migration, junction, and phosphorylation readouts","pmids":["19628037"],"confidence":"Medium","gaps":["Molecular basis of PAK2-to-PAK1 feedback undefined","Single-lab analysis"]},{"year":2009,"claim":"Identifying noncoding HGF mutations as the cause of DFNB39 and modeling both overexpression and conditional knockout in mice established HGF dosage as critical for cochlear function.","evidence":"DFNB39 locus sequencing, in vitro splicing assay, and transgenic overexpression plus conditional knockout mice with auditory phenotyping","pmids":["19576567"],"confidence":"High","gaps":["Cellular target of cochlear HGF not yet identified at this stage","Mechanism linking dosage to hair cell phenotype unresolved"]},{"year":2013,"claim":"Demonstrating that HGF-MET stabilizes ETS2 to form an MLL-ETS2 complex that deposits H3K4me3 on MMP promoters revealed a direct epigenetic route from receptor signaling to invasion-gene transcription.","evidence":"Reciprocal co-IP, ChIP for occupancy and H3K4me3, Mll-/- genetic loss-of-function, and invasion/metastasis assays","pmids":["23934123"],"confidence":"High","gaps":["How HGF signaling stabilizes ETS2 mechanistically not fully defined","Breadth of MLL-ETS2 target genes beyond MMP1/3 unknown"]},{"year":2014,"claim":"Showing that HGF confers MET-inhibitor resistance by restoring GAB1-mediated PI3K signaling explained a key therapeutic escape and validated HGF neutralization as a re-sensitizing strategy.","evidence":"Drug-sensitivity assays +/- HGF, tumor-stroma co-culture, human HGF knock-in xenografts, and phosphoprotein analysis","pmids":["25217525"],"confidence":"High","gaps":["Durability of HGF neutralization not addressed","Generality across MET-amplified contexts untested here"]},{"year":2015,"claim":"Identifying Arf6-dependent beta1 integrin recycling as required for HGF-driven endothelial angiogenesis extended MET signaling into vascular trafficking and tumor neovascularization.","evidence":"Endothelial conditional Arf6 knockout, integrin recycling assays, Arf6-GEF pharmacological inhibition, and in vivo tumor models","pmids":["26239146"],"confidence":"High","gaps":["Direct molecular link from MET to Arf6 GEF activation undefined","Selectivity of GEF inhibitors not fully characterized"]},{"year":2019,"claim":"Defining MET phosphorylation of PDHC (inhibiting) and GLS (activating), plus a Y1234-Y1235 LIR motif that drives autophagy when dephosphorylated, connected HGF/MET to metabolic reprogramming and a kinase-inhibitor escape mechanism.","evidence":"In vitro MET kinase assays on PDHC/GLS, metabolic flux, LIR mapping, MET Y1234/1235 mutagenesis, and liver cancer models","pmids":["30786811"],"confidence":"High","gaps":["Whether MET phosphorylates these substrates directly in vivo at physiologic levels not fully settled","Generality across tumor types untested"]},{"year":2019,"claim":"Demonstrating that LC3C selectively mediates autophagic degradation of MET defined a specific ATG8-family route controlling 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evidence for a pathogenetic role in tumourigenesis.","date":"2001","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11329134","citation_count":38,"is_preprint":false},{"pmid":"36109787","id":"PMC_36109787","title":"HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36109787","citation_count":38,"is_preprint":false},{"pmid":"23320110","id":"PMC_23320110","title":"HGF and c-Met interaction promotes migration in human chondrosarcoma cells.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23320110","citation_count":38,"is_preprint":false},{"pmid":"8380739","id":"PMC_8380739","title":"Molecular characteristics of HGF-SF and its role in cell motility and invasion.","date":"1993","source":"EXS","url":"https://pubmed.ncbi.nlm.nih.gov/8380739","citation_count":37,"is_preprint":false},{"pmid":"8527903","id":"PMC_8527903","title":"The Met-HGF/SF autocrine signaling mechanism is involved in sarcomagenesis.","date":"1995","source":"EXS","url":"https://pubmed.ncbi.nlm.nih.gov/8527903","citation_count":37,"is_preprint":false},{"pmid":"21327916","id":"PMC_21327916","title":"Novel therapy for myocardial infarction: can HGF/Met be beneficial?","date":"2011","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/21327916","citation_count":37,"is_preprint":false},{"pmid":"15149317","id":"PMC_15149317","title":"Electroporation-mediated HGF gene transfer ameliorated cyclosporine nephrotoxicity.","date":"2004","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/15149317","citation_count":37,"is_preprint":false},{"pmid":"10832594","id":"PMC_10832594","title":"Inhibition of HGF/SF-induced breast cancer cell motility and invasion by the HGF/SF variant, NK4.","date":"2000","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/10832594","citation_count":36,"is_preprint":false},{"pmid":"10588883","id":"PMC_10588883","title":"Hepatocyte growth factor (HGF) receptor expression and role of HGF during embryonic mouse testis development.","date":"1999","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10588883","citation_count":36,"is_preprint":false},{"pmid":"19628037","id":"PMC_19628037","title":"PAK1 and PAK2 have different roles in HGF-induced morphological responses.","date":"2009","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/19628037","citation_count":35,"is_preprint":false},{"pmid":"33066121","id":"PMC_33066121","title":"HGF/MET Signaling in Malignant Brain Tumors.","date":"2020","source":"International journal of molecular 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Inflammation.","date":"2020","source":"Journal of Crohn's & colitis","url":"https://pubmed.ncbi.nlm.nih.gov/32556102","citation_count":33,"is_preprint":false},{"pmid":"32943844","id":"PMC_32943844","title":"Emodin Retarded Renal Fibrosis Through Regulating HGF and TGFβ-Smad Signaling Pathway.","date":"2020","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32943844","citation_count":33,"is_preprint":false},{"pmid":"32152201","id":"PMC_32152201","title":"Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.","date":"2020","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32152201","citation_count":31,"is_preprint":false},{"pmid":"33123991","id":"PMC_33123991","title":"HGF/c-Met Signalling in the Tumor 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cDNA via baculovirus.\",\n      \"method\": \"Immunopurification binding assay, chemical cross-linking of radiolabelled ligand, tyrosine phosphorylation assay, baculovirus reconstitution in insect cells\",\n      \"journal\": \"EXS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (binding, cross-linking, phosphorylation, reconstitution) in a single study; independently corroborated across the corpus\",\n      \"pmids\": [\"8380735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"HGF/SF and human Scatter Factor are identical proteins encoded by a single gene on chromosome 7q11.2-21. A single-chain HGF-SF with destroyed protease cleavage site (Arg494→Gln) is largely inactive, demonstrating that proteolytic cleavage is essential for biological activity. The separately expressed light chain (serine protease homology domain) is inactive, while the heavy chain and an N-terminal/two-kringle splice variant can bind MET, stimulate its tyrosine phosphorylation, and induce cell dissociation but not mitogenesis.\",\n      \"method\": \"Protein sequencing, cDNA analysis, immunological comparison, transient expression of mutagenized cDNAs, receptor tyrosine phosphorylation assay, biological activity assays\",\n      \"journal\": \"EXS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis combined with functional assays and receptor activation readouts in a single focused study\",\n      \"pmids\": [\"8380739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"HGF receptor (p190MET) is a 190 kDa alpha-beta heterodimer of two disulfide-linked subunits derived from a 170 kDa precursor by glycosylation and proteolytic cleavage. The beta subunit contains the cytoplasmic tyrosine kinase domain; autophosphorylation at Tyr1235 upregulates kinase activity (increases Vmax). Negative regulation occurs via PKC activation or increased intracellular Ca2+, both leading to serine phosphorylation of the receptor and decreased kinase activity. The phosphorylated receptor associates Ras GAP, phospholipase C-gamma, src-related tyrosine kinase, and PI3-kinase in vitro.\",\n      \"method\": \"Biochemical receptor characterization, autophosphorylation mapping, mutagenesis, kinase activity assays, co-immunoprecipitation\",\n      \"journal\": \"EXS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical characterization of receptor structure and enzymatic mechanism with phosphorylation site mapping and multiple effector associations\",\n      \"pmids\": [\"8380735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"HGF-induced branching morphogenesis of MDCK cells in collagen gels is modulated by multiple phosphorylation mechanisms: PKC inhibition enhances branching; PKA activators and calmodulin antagonists reduce it; protein phosphatase inhibition (okadaic acid, calyculin A) markedly inhibits branching; and tyrosine kinase inhibition decreases branching, consistent with MET TK activity being required.\",\n      \"method\": \"MDCK collagen gel tubulogenesis assay with pharmacological kinase/phosphatase modulators\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean cellular morphogenesis assay with multiple pharmacological interventions, single lab\",\n      \"pmids\": [\"8405677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"After HGF-induced tyrosine phosphorylation of MET, the Shc adaptor protein binds via its SH2 domain to phosphotyrosines Y1349VHV and Y1356VNV on the receptor (Kd ~150 nM for both sites, measured by BIAcore). Shc is then phosphorylated on Y317VNV, generating a high-affinity Grb2 binding site (Kd ~15 nM), thereby amplifying Ras pathway activation. Overexpression of wild-type Shc (but not Y317F mutant) enhances HGF-stimulated cell migration and growth.\",\n      \"method\": \"Site-directed mutagenesis of HGF receptor, BIAcore biosensor binding kinetics with synthetic phosphopeptides and recombinant Shc, co-immunoprecipitation, overexpression of Shc mutants, motility and proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding kinetics plus site-directed mutagenesis plus functional rescue assays in a single rigorous study\",\n      \"pmids\": [\"7731718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The MET receptor signals through a two-phosphotyrosine 'multifunctional docking site' that simultaneously binds and activates multiple SH2-containing transducers including Ras and PI3-kinase, a feature shared with the related RON and SEA receptors and distinct from conventional growth factor receptors.\",\n      \"method\": \"Signal transduction analysis, receptor mutagenesis, biochemical characterization of docking site\",\n      \"journal\": \"Cytokine & growth factor reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review synthesis of receptor biochemistry established by the same group; docking site mechanism confirmed by mutagenesis in referenced primary work\",\n      \"pmids\": [\"9244408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Gab1 was identified as a direct-binding substrate of the c-Met receptor; Gab1 binds to c-Met phosphorylated on tyrosine residues via a proline-rich domain that interacts with the bidentate docking site. Expression of Gab1 in epithelial cells is sufficient to induce c-Met-specific branching tubulogenesis.\",\n      \"method\": \"Direct binding assay (immunoprecipitation), domain mapping, gain-of-function expression of Gab1 in epithelial cells with morphogenesis readout\",\n      \"journal\": \"Ciba Foundation symposium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and functional rescue experiments; single lab, abstract-level detail\",\n      \"pmids\": [\"9524774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Met-HGF/SF autocrine signaling activates the urokinase plasminogen proteolysis network, coupling Met signal transduction to extracellular matrix dissolution and enabling invasiveness and branching morphogenesis.\",\n      \"method\": \"Cell line models with autocrine Met-HGF/SF expression, in vitro invasiveness assays, biochemical pathway analysis\",\n      \"journal\": \"Ciba Foundation symposium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional demonstration in defined cell models with biochemical pathway linkage; single lab, abstract level\",\n      \"pmids\": [\"9524767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The single-chain HGF precursor is cleaved by specific serine proteases at the Arg494-Val495 bond to generate the biologically active alpha-beta heterodimer. HGF activator (HGFA), a coagulation factor XII-like serine proteinase, is critically involved in pericellular HGF activation; its activity is regulated by Kunitz-type transmembrane inhibitors HAI-1 and HAI-2, which also inhibit matriptase, plasmin, trypsin, and kallikreins.\",\n      \"method\": \"Biochemical identification of cleavage site, characterization of HGFA serine proteinase activity, identification and functional characterization of HAI-1 and HAI-2 inhibitors\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical cleavage site mapping and in vitro proteinase/inhibitor characterization; replicated across multiple studies in the corpus\",\n      \"pmids\": [\"10641789\", \"12784998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NK4 (comprising the N-terminal domain and four kringle domains of HGF) competitively antagonizes HGF binding to c-Met without activating it, blocking all HGF biological activities. NK4 also inhibits angiogenesis induced by VEGF and bFGF independently of its HGF-antagonist action, establishing it as a bifunctional molecule.\",\n      \"method\": \"Competitive receptor binding assay, biological activity assays (cell proliferation, scattering, invasion), in vivo angiogenesis models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding demonstrated with functional activity assays; angiogenesis inhibition confirmed in vivo; single lab\",\n      \"pmids\": [\"12824898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EphA kinase activation by ephrin-A1 negatively regulates HGF-induced branching morphogenesis in MDCK cells by inhibiting HGF-induced activation of Rac1 and PAK while retaining RhoA activation, leading to preservation of stress fibers. Dominant-negative RhoA or ROCK inhibitor (Y27632) reversed the ephrin-A1 inhibitory effect, placing Rho GTPase signaling downstream of both HGF/Met and EphA.\",\n      \"method\": \"Collagen gel branching morphogenesis assay, Rac1/RhoA GTPase pull-down assays, dominant-negative constructs, pharmacological ROCK inhibitor, live cell imaging of protrusion dynamics\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal genetic and pharmacological tools with GTPase biochemistry; rigorous epistasis established\",\n      \"pmids\": [\"14517207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PKCepsilon controls HGF/c-Met signaling to the ERK cascade specifically within endosomal compartments, causing ERK accumulation in focal complexes. PKCalpha controls subsequent microtubule-dependent sorting of c-Met to a perinuclear destination. Endosomal traffic is essential for HGF/c-Met to trigger an ERK response, and PKCepsilon-dependent dynamic properties of this endosomal signaling are required for normal HGF-dependent cell migration.\",\n      \"method\": \"Live cell imaging, subcellular fractionation, pharmacological and dominant-negative PKC isotype manipulation, ERK localization by immunofluorescence, migration assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct localization experiments tied to signaling and functional consequences, with isotype-specific PKC dissection; multiple orthogonal methods\",\n      \"pmids\": [\"15385963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HGF disrupts ErbB2/NeuNT-induced epithelial morphogenesis in MDCK cells, stimulating breakdown of cell-cell junctions (loss of claudin-1 and E-cadherin, internalization of ZO-1) and promoting single-cell invasion. This process requires MEK-dependent signaling downstream of HGF/Met, as MEK inhibition restores junctional E-cadherin and ZO-1 and abrogates HGF-induced invasion.\",\n      \"method\": \"3D MDCK collagen culture invasion assay, MEK pharmacological inhibitor, immunofluorescence of junctional proteins, cell biology readouts\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional invasion assay with pharmacological pathway dissection and molecular marker readouts; single lab\",\n      \"pmids\": [\"15548598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HGF induces CXCR4 expression and CXCL12-dependent invasion in MCF-7 breast cancer cells through the MAPK1/ERK1/2 pathway activating Ets1 transcription factor, and through NF-kappaB. Dominant-negative constructs and inhibitors of Ets1 and NF-kappaB block HGF-induced CXCR4 transcription and chemoinvasion.\",\n      \"method\": \"Reporter gene assay (CXCR4 promoter luciferase), dominant-negative transcription factor constructs, pharmacological inhibitors, EMSA/DNA binding assays, chemoinvasion assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus dominant-negative constructs plus inhibitors; single lab\",\n      \"pmids\": [\"16840440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In prostate cancer cells, PAK4 binds to and phosphorylates LIMK1 in an HGF-dependent manner. PAK4 expression levels regulate cofilin phosphorylation (via LIMK1 activity), and PAK4 and LIMK1 interact at the cell periphery (demonstrated by FRET:FLIM). HGF-stimulated cell migration requires a cofilin phosphorylation step mediated by PAK4.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (PAK4 phosphorylation of LIMK1), FRET:FLIM for protein-protein interaction in live cells, siRNA knockdown, cofilin phosphorylation western blot, migration assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay plus FRET:FLIM plus functional migration assay; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"18424072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PAK1 and PAK2 have distinct roles downstream of HGF: PAK1 knockdown inhibits HGF-stimulated migration and loss of cell-cell junctions, whereas PAK2 knockdown enhances junction loss and lamellipodia extension without affecting migration speed. PAK2 provides negative feedback on PAK1 phosphorylation.\",\n      \"method\": \"siRNA knockdown of PAK1/PAK2, HGF-stimulated migration assay, immunofluorescence of cell-cell junctions, phosphorylation western blot\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific siRNA knockdown with multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"19628037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Noncoding mutations in HGF (two intronic deletions in a highly conserved sequence that is part of the 3'UTR of a short HGF isoform, and a silent exon 5 substitution affecting splicing) cause autosomal-recessive nonsyndromic hearing loss DFNB39. Mouse models of Hgf overexpression cause progressive outer hair cell degeneration; cochlear-specific Hgf conditional knockout causes general cochlear dysplasia.\",\n      \"method\": \"Sequencing of DFNB39 locus, in vitro splicing assay, mouse transgenic overexpression and conditional knockout models with auditory phenotyping\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetic mapping plus functional splicing assay plus two independent mouse models with defined cochlear phenotypes\",\n      \"pmids\": [\"19576567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HGF-MET signaling results in accumulation of ETS2, which interacts with MLL to form a complex that transactivates MMP1 and MMP3. ChIP assays showed that HGF-MET pathway activation increases occupancy of the MLL-ETS2 complex on MMP1/MMP3 promoters and MLL-mediated H3K4 trimethylation, activating transcription. This epigenetic mechanism is required for HGF-induced hepatocellular carcinoma invasion and metastatic growth.\",\n      \"method\": \"Co-immunoprecipitation (MLL-ETS2 interaction), ChIP assay (promoter occupancy and H3K4me3), loss-of-function (MLL knockout cells/mice), invasion and metastasis assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal co-IP, ChIP, and genetic (Mll-/- mice) validation of epigenetic mechanism downstream of HGF-MET; multiple orthogonal methods\",\n      \"pmids\": [\"23934123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HGF-induced resistance to MET kinase inhibitors in MET-amplified tumors is mediated by restoration of physiologic GAB1-mediated PI3K activation that compensates for loss of aberrant HER3-dependent PI3K signaling. HGF neutralization (ficlatuzumab) restores sensitivity to MET-targeted agents both in co-culture systems and in human HGF knock-in mice bearing MET-amplified tumors.\",\n      \"method\": \"Cell-based drug sensitivity assays +/- HGF, stroma-tumor co-culture system, human HGF knock-in mouse xenograft model, phosphoprotein signaling analysis (GAB1/PI3K/HER3), neutralizing antibody experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanism dissected in multiple complementary models (in vitro, co-culture, in vivo knock-in mouse) with defined signaling mechanism\",\n      \"pmids\": [\"25217525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Arf6 is required for HGF-induced beta1 integrin recycling in endothelial cells and for HGF-dependent tumor neoangiogenesis and growth. Endothelial-specific Arf6 deletion abolishes HGF-stimulated beta1 integrin recycling. The Arf6 GEF Grp1 (as well as GEP100, EFA6B, EFA6D) regulates HGF-stimulated beta1 integrin recycling and can be pharmacologically inhibited to suppress tumor vascularization.\",\n      \"method\": \"Endothelial cell-targeted conditional knockout mice, beta1 integrin recycling assay, pharmacological Arf6 GEF inhibition, in vivo tumor angiogenesis and growth models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (conditional KO) plus pharmacological inhibition plus mechanistic recycling assay in vivo and in vitro; multiple orthogonal approaches\",\n      \"pmids\": [\"26239146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HGF activates MET kinase, which phosphorylates the pyruvate dehydrogenase complex (PDHC) to inhibit its activity and phosphorylates GLS/GLS1 (glutaminase) to activate it, promoting the Warburg effect and glutaminolysis for cancer cell biogenesis. The key kinase activation residues Y1234/Y1235 in MET also constitute an LC3-interacting region (LIR) motif (Y1234-Y1235-x-V1237); when dephosphorylated (upon MET kinase inhibition), MET induces autophagy via this LIR motif to maintain biogenesis, representing an escape mechanism.\",\n      \"method\": \"In vitro kinase assay (MET phosphorylation of PDHC and GLS), metabolic flux analysis, LC3-interacting region mapping, autophagy assays, MET Y1234/1235 mutagenesis, in vitro and in vivo liver cancer models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay identifying PDHC and GLS as MET substrates, LIR motif mapping, mutagenesis, and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"30786811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAP1LC3C (LC3C) selectively mediates autophagic degradation of the Met receptor via direct complex formation between Met and LC3C. LC3C deletion abrogates Met entry into the autophagy-dependent degradative pathway, resulting in enhanced Met stability, signaling, and cell invasion. This establishes a distinct role for LC3C among ATG8 family members in Met RTK downregulation.\",\n      \"method\": \"LC3C knockout (CRISPR), co-immunoprecipitation (Met-LC3C complex), domain mapping (LC3C domains required for rescue), Met stability and degradation assays, invasion assays in cancer cells with low LC3C\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO plus reciprocal co-IP plus domain rescue experiments plus functional invasion readout; multiple orthogonal methods\",\n      \"pmids\": [\"31851933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In the inner ear, HGF is required for neural crest cell migration into the stria vascularis intermediate layer during development. A 10-bp noncoding intronic deletion (del10) in Hgf reduces cochlear HGF levels, causing failure of neural crest infiltration into the stria vascularis, reduced endocochlear potential, and consequent moderate-to-profound hearing loss recapitulating human DFNB39 deafness.\",\n      \"method\": \"Mouse model with engineered noncoding Hgf deletion, auditory brainstem response (tone burst ABR), endocochlear potential measurement, immunohistochemistry for neural crest cell migration in stria vascularis, RNAseq\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetically engineered mouse model with direct physiological (EP measurement) and cellular (IHC neural crest migration) mechanistic readouts; independent replication of DFNB39 findings\",\n      \"pmids\": [\"32152201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HGF activates PI3-kinase and its downstream target p70 S6 kinase in corneal epithelial cells. PKC is involved in the PI3K-dependent (but not MAPK-dependent) activation of p70 S6K. Inhibition of PI3K (wortmannin) or p70 S6K (rapamycin) blocks HGF-promoted corneal epithelial wound healing in organ culture.\",\n      \"method\": \"PI3K activity assay, p70 S6K immunoprecipitation kinase assay, pharmacological inhibitors (wortmannin, rapamycin, calphostin C, PD98059), corneal epithelial wound healing organ culture model\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase activity assays with pharmacological dissection and functional wound healing readout; single lab\",\n      \"pmids\": [\"11446769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HGF induces MAP kinase-dependent ARPE-19 cell migration accompanied by tyrosine phosphorylation of both the HGF receptor (c-met) and beta-catenin, increased cytosolic levels of beta-catenin, and transactivation activity of beta-catenin. Both beta-catenin and MAP kinases are components of the HGF-induced RPE migration pathway.\",\n      \"method\": \"Quantitative migration assay, immunoprecipitation/western blot for HGF receptor and beta-catenin phosphorylation, beta-catenin luciferase reporter (transactivation), MEK inhibitor (MAP kinase pathway inhibition), immunofluorescence\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assays plus reporter assay plus pharmacological dissection; single lab\",\n      \"pmids\": [\"12500177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HGF activates c-MET-ERK1/2-ELK1 signaling to upregulate ETV1 expression, which in turn transcriptionally activates PTK2 (FAK) and MET itself, creating a positive feedback loop. ETV1 ChIP occupancy on PTK2 and MET promoters was demonstrated, and inhibiting PTK2 or c-MET downstream of ETV1 decreased ETV1-mediated HCC metastasis.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP) for ETV1 on PTK2 and MET promoters, western blot for signaling intermediates, transwell invasion assay, orthotopic metastatic mouse model, siRNA knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus in vivo model; single lab, abstract-level detail\",\n      \"pmids\": [\"36109787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HGF is a mesenchymally secreted, proteolytically activated (at Arg494-Val495 by serine proteases including HGFA) alpha-beta heterodimeric ligand that binds and activates the MET receptor tyrosine kinase, triggering autophosphorylation at Tyr1235 (among other sites) and recruitment of multiple SH2-domain effectors (including Shc→Grb2/Ras, PI3K, Gab1, PLC-gamma) through a bidentate multifunctional docking site; activated MET signals through endosomal compartments (regulated by PKCepsilon/PKCalpha), controls Rho GTPases (Rac1, Cdc42, RhoA) and downstream kinases (PAK1, PAK2, PAK4-LIMK1-cofilin) to drive cell proliferation, migration, scattering, and branching morphogenesis; phosphorylates metabolic enzymes PDHC (inhibiting) and GLS (activating) to reprogram cancer metabolism; engages an MLL-ETS2 epigenetic complex to activate MMP transcription; is degraded via LC3C-mediated selective autophagy; and in the inner ear signals through MET to direct neural crest cell migration into the stria vascularis, with fine-tuned HGF levels being essential for normal hearing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HGF is a mesenchymally derived secreted ligand that controls epithelial proliferation, migration, scattering, and branching morphogenesis by binding and activating the MET receptor tyrosine kinase (p190MET) [#0, #2]. HGF is synthesized as an inactive single-chain precursor that must be proteolytically cleaved at the Arg494-Val495 bond to form the active disulfide-linked alpha-beta heterodimer; a cleavage-site mutant is largely inactive, and pericellular activation is carried out by serine proteases such as HGF activator (HGFA), which is itself restrained by the Kunitz-type inhibitors HAI-1 and HAI-2 [#1, #8]. Ligand binding drives MET autophosphorylation at Tyr1235 and assembles a bidentate two-phosphotyrosine docking site that simultaneously recruits multiple SH2-domain effectors, including Shc (which amplifies Ras/Grb2 signaling), PI3-kinase, PLC-gamma, and Gab1, the latter being sufficient to drive MET-specific branching tubulogenesis [#2, #4, #5, #6]. Downstream, HGF/MET signaling routes through endosomal compartments under PKCepsilon/PKCalpha control to sustain ERK responses required for migration, and engages Rho-family GTPases (Rac1, RhoA) and the PAK4-LIMK1-cofilin axis to remodel the cytoskeleton, dissolve cell-cell junctions, and promote invasion [#11, #10, #14, #12]. HGF/MET drives invasive and metastatic programs through transcriptional and epigenetic outputs, activating the urokinase proteolysis network, inducing CXCR4 and ETV1-dependent feedback loops, and assembling an MLL-ETS2 complex that deposits H3K4me3 to transactivate MMP1/MMP3 [#7, #13, #17, #25]. MET also reprograms cancer metabolism by phosphorylating and inhibiting the pyruvate dehydrogenase complex while activating glutaminase, and is itself downregulated by LC3C-mediated selective autophagy [#20, #21]. In development, fine-tuned cochlear HGF levels are required for neural crest migration into the stria vascularis; noncoding HGF mutations that perturb these levels cause autosomal-recessive nonsyndromic hearing loss DFNB39 [#16, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that HGF is the physiological ligand for the MET proto-oncogene product defined the entire downstream signaling system and linked a secreted growth factor to an oncogenic receptor.\",\n      \"evidence\": \"Binding, chemical cross-linking, receptor phosphorylation, and baculovirus reconstitution of MET in insect cells\",\n      \"pmids\": [\"8380735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the active HGF-MET complex not resolved here\", \"Structural basis of high-affinity binding not defined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrating that proteolytic cleavage at Arg494-Val495 converts inactive single-chain HGF into the active heterodimer answered how HGF activity is post-translationally gated, and dissected which chains carry binding versus mitogenic function.\",\n      \"evidence\": \"Protein sequencing, mutagenesis of the cleavage site, and functional/receptor-activation assays on separated chains\",\n      \"pmids\": [\"8380739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the activating protease not yet established\", \"Mechanism by which the heavy chain alone activates MET but not mitogenesis unclear\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Biochemical characterization of MET as an alpha-beta heterodimer with Tyr1235 autophosphorylation upregulating kinase activity, plus negative regulation via PKC/Ca2+ serine phosphorylation, established the receptor's catalytic mechanism and its in vitro effector associations.\",\n      \"evidence\": \"Receptor characterization, autophosphorylation mapping, kinase assays, and co-immunoprecipitation of RasGAP, PLC-gamma, Src, PI3K\",\n      \"pmids\": [\"8380735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro associations not yet validated as functional in cells\", \"Hierarchy of effector recruitment undefined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Quantifying Shc binding to MET phosphotyrosines Y1349/Y1356 and the Shc-Y317-generated Grb2 site clarified how HGF amplifies Ras pathway output and links receptor docking to migration and growth.\",\n      \"evidence\": \"BIAcore phosphopeptide kinetics, receptor and Shc mutagenesis, co-IP, and motility/proliferation rescue assays\",\n      \"pmids\": [\"7731718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of Shc versus other docking effectors not quantified\", \"Downstream Ras effector specificity not addressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defining the two-phosphotyrosine 'multifunctional docking site' and identifying Gab1 as a direct binder sufficient to drive branching tubulogenesis explained how a single receptor coordinates multiple transducers for morphogenesis.\",\n      \"evidence\": \"Docking-site mutagenesis, direct binding/domain mapping, and gain-of-function Gab1 expression with morphogenesis readout\",\n      \"pmids\": [\"9244408\", \"9524774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gab1 findings at abstract-level detail from a single lab\", \"Whether Gab1 recruitment is direct or PI3K/Grb2-bridged not fully resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linking autocrine Met-HGF signaling to the urokinase plasminogen network coupled receptor activation to extracellular matrix dissolution, providing a mechanism for invasiveness.\",\n      \"evidence\": \"Autocrine cell-line models with invasiveness assays and biochemical pathway analysis\",\n      \"pmids\": [\"9524767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets within the uPA network not identified here\", \"Single-lab, abstract-level detail\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying HGFA as the critical pericellular activating serine protease and HAI-1/HAI-2 as its inhibitors mapped the proteolytic control circuit that governs where and when HGF is activated.\",\n      \"evidence\": \"Cleavage-site mapping, HGFA proteinase characterization, and functional analysis of HAI-1/HAI-2 inhibitors\",\n      \"pmids\": [\"10641789\", \"12784998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of HGFA versus other proteases unquantified\", \"Spatial regulation of inhibitor activity not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing HGF activates PI3K and p70 S6K to drive corneal epithelial wound healing extended MET signaling to a regenerative, translational-control output and placed PKC upstream of the PI3K-dependent arm.\",\n      \"evidence\": \"PI3K and p70 S6K kinase assays with wortmannin/rapamycin/PKC inhibitors in a corneal wound-healing organ culture\",\n      \"pmids\": [\"11446769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PI3K-to-S6K linkage inferred pharmacologically\", \"Single-lab tissue model\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating HGF-induced beta-catenin tyrosine phosphorylation and transactivation in RPE cells linked MET signaling to a transcriptional effector during migration.\",\n      \"evidence\": \"Migration assay, phospho-IP/western blot, beta-catenin luciferase reporter, and MEK inhibition\",\n      \"pmids\": [\"12500177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct beta-catenin target genes not identified\", \"Single-lab cell model\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping EphA/ephrin-A1 antagonism of HGF branching onto Rac1/PAK suppression with retained RhoA defined how counter-signals balance the cytoskeletal output of MET.\",\n      \"evidence\": \"Branching morphogenesis assays, GTPase pull-downs, dominant-negative RhoA, and ROCK inhibitor epistasis\",\n      \"pmids\": [\"14517207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular node where EphA intersects HGF signaling not pinpointed\", \"In vivo relevance of the cross-talk untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Characterizing NK4 as a competitive MET antagonist that also independently blocks angiogenesis established a bifunctional inhibitory tool and reinforced the receptor-binding map.\",\n      \"evidence\": \"Competitive binding, biological activity assays, and in vivo angiogenesis models\",\n      \"pmids\": [\"12824898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/target mediating the HGF-independent anti-angiogenic effect undefined\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that HGF/MET requires PKCepsilon/PKCalpha-controlled endosomal trafficking to generate localized ERK signaling reframed MET output as spatially compartmentalized and essential for migration.\",\n      \"evidence\": \"Live imaging, subcellular fractionation, isotype-specific PKC manipulation, and migration assays\",\n      \"pmids\": [\"15385963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endosomal sorting machinery beyond PKC isotypes not defined\", \"Connection to specific migration effectors not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that HGF overrides ErbB2-driven morphogenesis by dissolving junctions through MEK-dependent signaling explained how MET converts coherent epithelia into single-cell invaders.\",\n      \"evidence\": \"3D MDCK invasion assay with MEK inhibition and junctional-protein immunofluorescence\",\n      \"pmids\": [\"15548598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MEK targets at junctions not identified\", \"Single-lab cell model\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking HGF to ERK-Ets1 and NF-kappaB transcriptional induction of CXCR4 connected MET activation to chemokine-driven invasion programs.\",\n      \"evidence\": \"CXCR4 promoter reporter, dominant-negative Ets1/NF-kappaB, EMSA, and chemoinvasion assays\",\n      \"pmids\": [\"16840440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy versus indirect effects not fully resolved\", \"Single-lab cell model\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing the HGF-dependent PAK4-LIMK1-cofilin phosphorylation cascade at the cell periphery defined a concrete cytoskeletal mechanism for MET-driven migration.\",\n      \"evidence\": \"Co-IP, in vitro PAK4 kinase assay on LIMK1, FRET:FLIM, siRNA, and migration assays\",\n      \"pmids\": [\"18424072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream link from MET to PAK4 activation not detailed\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Dissecting opposing PAK1 versus PAK2 roles downstream of HGF revealed antagonistic regulation of migration and junction stability, with PAK2 providing negative feedback on PAK1.\",\n      \"evidence\": \"PAK1/PAK2 siRNA knockdown with migration, junction, and phosphorylation readouts\",\n      \"pmids\": [\"19628037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of PAK2-to-PAK1 feedback undefined\", \"Single-lab analysis\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying noncoding HGF mutations as the cause of DFNB39 and modeling both overexpression and conditional knockout in mice established HGF dosage as critical for cochlear function.\",\n      \"evidence\": \"DFNB39 locus sequencing, in vitro splicing assay, and transgenic overexpression plus conditional knockout mice with auditory phenotyping\",\n      \"pmids\": [\"19576567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular target of cochlear HGF not yet identified at this stage\", \"Mechanism linking dosage to hair cell phenotype unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that HGF-MET stabilizes ETS2 to form an MLL-ETS2 complex that deposits H3K4me3 on MMP promoters revealed a direct epigenetic route from receptor signaling to invasion-gene transcription.\",\n      \"evidence\": \"Reciprocal co-IP, ChIP for occupancy and H3K4me3, Mll-/- genetic loss-of-function, and invasion/metastasis assays\",\n      \"pmids\": [\"23934123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HGF signaling stabilizes ETS2 mechanistically not fully defined\", \"Breadth of MLL-ETS2 target genes beyond MMP1/3 unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that HGF confers MET-inhibitor resistance by restoring GAB1-mediated PI3K signaling explained a key therapeutic escape and validated HGF neutralization as a re-sensitizing strategy.\",\n      \"evidence\": \"Drug-sensitivity assays +/- HGF, tumor-stroma co-culture, human HGF knock-in xenografts, and phosphoprotein analysis\",\n      \"pmids\": [\"25217525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability of HGF neutralization not addressed\", \"Generality across MET-amplified contexts untested here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying Arf6-dependent beta1 integrin recycling as required for HGF-driven endothelial angiogenesis extended MET signaling into vascular trafficking and tumor neovascularization.\",\n      \"evidence\": \"Endothelial conditional Arf6 knockout, integrin recycling assays, Arf6-GEF pharmacological inhibition, and in vivo tumor models\",\n      \"pmids\": [\"26239146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from MET to Arf6 GEF activation undefined\", \"Selectivity of GEF inhibitors not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining MET phosphorylation of PDHC (inhibiting) and GLS (activating), plus a Y1234-Y1235 LIR motif that drives autophagy when dephosphorylated, connected HGF/MET to metabolic reprogramming and a kinase-inhibitor escape mechanism.\",\n      \"evidence\": \"In vitro MET kinase assays on PDHC/GLS, metabolic flux, LIR mapping, MET Y1234/1235 mutagenesis, and liver cancer models\",\n      \"pmids\": [\"30786811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MET phosphorylates these substrates directly in vivo at physiologic levels not fully settled\", \"Generality across tumor types untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that LC3C selectively mediates autophagic degradation of MET defined a specific ATG8-family route controlling receptor stability, signaling, and invasion.\",\n      \"evidence\": \"LC3C CRISPR knockout, reciprocal Met-LC3C co-IP, domain-rescue mapping, and degradation/invasion assays\",\n      \"pmids\": [\"31851933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that initiates MET-LC3C selective autophagy unclear\", \"Relationship to the Y1234/Y1235 LIR mechanism not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that a noncoding Hgf deletion reduces cochlear HGF, blocking neural crest migration into the stria vascularis and lowering endocochlear potential, defined the developmental cellular mechanism of DFNB39 deafness.\",\n      \"evidence\": \"Engineered noncoding Hgf-deletion mouse with ABR, endocochlear potential measurement, neural crest IHC, and RNAseq\",\n      \"pmids\": [\"32152201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether neural crest cells respond to HGF via MET directly in vivo not shown here\", \"How precise HGF dosage is set transcriptionally not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping an HGF-MET-ERK-ELK1-ETV1 axis that transactivates PTK2/FAK and MET itself revealed a positive feedback loop sustaining HCC metastasis.\",\n      \"evidence\": \"Reporter assays, ETV1 ChIP on PTK2/MET promoters, signaling western blots, invasion assays, and orthotopic metastasis model\",\n      \"pmids\": [\"36109787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of the feedback loop to tumor growth not isolated\", \"Single-lab, abstract-level detail\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse MET-proximal effector branches (docking-site adaptors, endosomal PKC control, Rho/PAK cytoskeletal modules, metabolic substrates, autophagy, and transcriptional/epigenetic outputs) are integrated and prioritized in a given cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking spatial signaling to specific transcriptional outputs\", \"Context-dependent weighting of effector branches not defined\", \"In vivo physiologic versus oncogenic signaling differences incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 16, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 18, 20]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20, 21]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7, 17]}\n    ],\n    \"complexes\": [\"MLL-ETS2 complex\"],\n    \"partners\": [\"MET\", \"HGFA\", \"SPINT1\", \"SPINT2\", \"GAB1\", \"SHC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}