Affinage

HGF

Hepatocyte growth factor · UniProt P14210

Length
728 aa
Mass
83.1 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1993 High

    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

    PMID:8380735

    Open questions at the time
    • Stoichiometry of the active HGF-MET complex not resolved here
    • Structural basis of high-affinity binding not defined
  2. 1993 High

    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

    PMID:8380739

    Open questions at the time
    • Identity of the activating protease not yet established
    • Mechanism by which the heavy chain alone activates MET but not mitogenesis unclear
  3. 1993 High

    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

    PMID:8380735

    Open questions at the time
    • In vitro associations not yet validated as functional in cells
    • Hierarchy of effector recruitment undefined
  4. 1995 High

    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

    PMID:7731718

    Open questions at the time
    • Relative contribution of Shc versus other docking effectors not quantified
    • Downstream Ras effector specificity not addressed
  5. 1997 Medium

    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

    PMID:9244408 PMID:9524774

    Open questions at the time
    • Gab1 findings at abstract-level detail from a single lab
    • Whether Gab1 recruitment is direct or PI3K/Grb2-bridged not fully resolved
  6. 1997 Medium

    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

    PMID:9524767

    Open questions at the time
    • Direct transcriptional targets within the uPA network not identified here
    • Single-lab, abstract-level detail
  7. 1999 High

    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

    PMID:10641789 PMID:12784998

    Open questions at the time
    • Relative in vivo contribution of HGFA versus other proteases unquantified
    • Spatial regulation of inhibitor activity not resolved
  8. 2001 Medium

    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

    PMID:11446769

    Open questions at the time
    • Direct PI3K-to-S6K linkage inferred pharmacologically
    • Single-lab tissue model
  9. 2002 Medium

    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

    PMID:12500177

    Open questions at the time
    • Direct beta-catenin target genes not identified
    • Single-lab cell model
  10. 2003 High

    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

    PMID:14517207

    Open questions at the time
    • Molecular node where EphA intersects HGF signaling not pinpointed
    • In vivo relevance of the cross-talk untested
  11. 2003 Medium

    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

    PMID:12824898

    Open questions at the time
    • Receptor/target mediating the HGF-independent anti-angiogenic effect undefined
    • Single-lab characterization
  12. 2004 High

    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

    PMID:15385963

    Open questions at the time
    • Endosomal sorting machinery beyond PKC isotypes not defined
    • Connection to specific migration effectors not mapped
  13. 2004 Medium

    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

    PMID:15548598

    Open questions at the time
    • Direct MEK targets at junctions not identified
    • Single-lab cell model
  14. 2006 Medium

    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

    PMID:16840440

    Open questions at the time
    • Direct promoter occupancy versus indirect effects not fully resolved
    • Single-lab cell model
  15. 2008 High

    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

    PMID:18424072

    Open questions at the time
    • Upstream link from MET to PAK4 activation not detailed
    • In vivo relevance untested
  16. 2009 Medium

    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

    PMID:19628037

    Open questions at the time
    • Molecular basis of PAK2-to-PAK1 feedback undefined
    • Single-lab analysis
  17. 2009 High

    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

    PMID:19576567

    Open questions at the time
    • Cellular target of cochlear HGF not yet identified at this stage
    • Mechanism linking dosage to hair cell phenotype unresolved
  18. 2013 High

    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

    PMID:23934123

    Open questions at the time
    • How HGF signaling stabilizes ETS2 mechanistically not fully defined
    • Breadth of MLL-ETS2 target genes beyond MMP1/3 unknown
  19. 2014 High

    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

    PMID:25217525

    Open questions at the time
    • Durability of HGF neutralization not addressed
    • Generality across MET-amplified contexts untested here
  20. 2015 High

    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

    PMID:26239146

    Open questions at the time
    • Direct molecular link from MET to Arf6 GEF activation undefined
    • Selectivity of GEF inhibitors not fully characterized
  21. 2019 High

    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

    PMID:30786811

    Open questions at the time
    • Whether MET phosphorylates these substrates directly in vivo at physiologic levels not fully settled
    • Generality across tumor types untested
  22. 2019 High

    Demonstrating that LC3C selectively mediates autophagic degradation of MET defined a specific ATG8-family route controlling receptor stability, signaling, and invasion.

    Evidence LC3C CRISPR knockout, reciprocal Met-LC3C co-IP, domain-rescue mapping, and degradation/invasion assays

    PMID:31851933

    Open questions at the time
    • Trigger that initiates MET-LC3C selective autophagy unclear
    • Relationship to the Y1234/Y1235 LIR mechanism not integrated
  23. 2020 High

    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.

    Evidence Engineered noncoding Hgf-deletion mouse with ABR, endocochlear potential measurement, neural crest IHC, and RNAseq

    PMID:32152201

    Open questions at the time
    • Whether neural crest cells respond to HGF via MET directly in vivo not shown here
    • How precise HGF dosage is set transcriptionally not resolved
  24. 2022 Medium

    Mapping an HGF-MET-ERK-ELK1-ETV1 axis that transactivates PTK2/FAK and MET itself revealed a positive feedback loop sustaining HCC metastasis.

    Evidence Reporter assays, ETV1 ChIP on PTK2/MET promoters, signaling western blots, invasion assays, and orthotopic metastasis model

    PMID:36109787

    Open questions at the time
    • Quantitative contribution of the feedback loop to tumor growth not isolated
    • Single-lab, abstract-level detail

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-9612973 Autophagy 2
Partners
GAB1HGFAMETSHC1SPINT1SPINT2
Complex memberships
MLL-ETS2 complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 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. Immunopurification binding assay, chemical cross-linking of radiolabelled ligand, tyrosine phosphorylation assay, baculovirus reconstitution in insect cells EXS High 8380735
1993 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. Protein sequencing, cDNA analysis, immunological comparison, transient expression of mutagenized cDNAs, receptor tyrosine phosphorylation assay, biological activity assays EXS High 8380739
1993 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. Biochemical receptor characterization, autophosphorylation mapping, mutagenesis, kinase activity assays, co-immunoprecipitation EXS High 8380735
1993 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. MDCK collagen gel tubulogenesis assay with pharmacological kinase/phosphatase modulators Developmental biology Medium 8405677
1995 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. 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 Oncogene High 7731718
1997 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. Signal transduction analysis, receptor mutagenesis, biochemical characterization of docking site Cytokine & growth factor reviews Medium 9244408
1997 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. Direct binding assay (immunoprecipitation), domain mapping, gain-of-function expression of Gab1 in epithelial cells with morphogenesis readout Ciba Foundation symposium Medium 9524774
1997 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. Cell line models with autocrine Met-HGF/SF expression, in vitro invasiveness assays, biochemical pathway analysis Ciba Foundation symposium Medium 9524767
1999 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. Biochemical identification of cleavage site, characterization of HGFA serine proteinase activity, identification and functional characterization of HAI-1 and HAI-2 inhibitors The international journal of biochemistry & cell biology High 10641789 12784998
2003 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. Competitive receptor binding assay, biological activity assays (cell proliferation, scattering, invasion), in vivo angiogenesis models Cancer science Medium 12824898
2003 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. Collagen gel branching morphogenesis assay, Rac1/RhoA GTPase pull-down assays, dominant-negative constructs, pharmacological ROCK inhibitor, live cell imaging of protrusion dynamics The Journal of cell biology High 14517207
2004 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. Live cell imaging, subcellular fractionation, pharmacological and dominant-negative PKC isotype manipulation, ERK localization by immunofluorescence, migration assays The EMBO journal High 15385963
2004 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. 3D MDCK collagen culture invasion assay, MEK pharmacological inhibitor, immunofluorescence of junctional proteins, cell biology readouts Molecular biology of the cell Medium 15548598
2006 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. Reporter gene assay (CXCR4 promoter luciferase), dominant-negative transcription factor constructs, pharmacological inhibitors, EMSA/DNA binding assays, chemoinvasion assay Carcinogenesis Medium 16840440
2008 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. 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 Cellular signalling High 18424072
2009 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. siRNA knockdown of PAK1/PAK2, HGF-stimulated migration assay, immunofluorescence of cell-cell junctions, phosphorylation western blot Cellular signalling Medium 19628037
2009 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. Sequencing of DFNB39 locus, in vitro splicing assay, mouse transgenic overexpression and conditional knockout models with auditory phenotyping American journal of human genetics High 19576567
2013 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. Co-immunoprecipitation (MLL-ETS2 interaction), ChIP assay (promoter occupancy and H3K4me3), loss-of-function (MLL knockout cells/mice), invasion and metastasis assays The Journal of clinical investigation High 23934123
2014 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. 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 Cancer research High 25217525
2015 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. Endothelial cell-targeted conditional knockout mice, beta1 integrin recycling assay, pharmacological Arf6 GEF inhibition, in vivo tumor angiogenesis and growth models Nature communications High 26239146
2019 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. 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 Autophagy High 30786811
2019 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. 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 Cell reports High 31851933
2020 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. 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 The Journal of neuroscience High 32152201
2001 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. PI3K activity assay, p70 S6K immunoprecipitation kinase assay, pharmacological inhibitors (wortmannin, rapamycin, calphostin C, PD98059), corneal epithelial wound healing organ culture model Experimental eye research Medium 11446769
2002 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. 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 Molecular vision Medium 12500177
2022 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. 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 of experimental & clinical cancer research Medium 36109787

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Expression of the Met/HGF receptor in normal and neoplastic human tissues. Oncogene 484 1719465
2010 The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proceedings of the Japan Academy. Series B, Physical and biological sciences 405 20551596
1994 RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. The EMBO journal 280 8062829
2013 Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 252 23388504
2012 Targeting the HGF/Met signaling pathway in cancer therapy. Expert opinion on therapeutic targets 186 22530990
2019 The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. Autophagy 171 30786811
1995 The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene 171 7731718
2010 Targeting the HGF/Met signalling pathway in cancer. European journal of cancer (Oxford, England : 1990) 166 20303741
1995 Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor. Brain research. Molecular brain research 162 7500831
2013 The emerging role of MET/HGF inhibitors in oncology. Cancer treatment reviews 161 23453860
2015 Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. Clinical science (London, England : 1979) 132 26561593
1999 HGF: a multifunctional growth factor controlling cell scattering. The international journal of biochemistry & cell biology 128 10641789
1996 Overexpression of the met/HGF receptor in renal cell carcinomas. International journal of cancer 126 8682590
2003 NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer science 124 12824898
2008 A PAK4-LIMK1 pathway drives prostate cancer cell migration downstream of HGF. Cellular signalling 123 18424072
2004 PKC controls HGF-dependent c-Met traffic, signalling and cell migration. The EMBO journal 122 15385963
2022 HGF/c-Met: A Key Promoter in Liver Regeneration. Frontiers in pharmacology 117 35370682
1997 Met-HGF/SF: tumorigenesis, invasion and metastasis. Ciba Foundation symposium 115 9524767
2000 The branchial arches and HGF are growth-promoting and chemoattractant for cranial motor axons. Development (Cambridge, England) 111 10725250
2003 Roles of hepatocyte growth factor (HGF) activator and HGF activator inhibitor in the pericellular activation of HGF/scatter factor. Cancer metastasis reviews 110 12784998
2015 Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion. Molecular cancer 107 25971889
2011 HGF-independent potentiation of EGFR action by c-Met. Oncogene 99 21423210
2021 HGF and MET: From Brain Development to Neurological Disorders. Frontiers in cell and developmental biology 96 34179015
2008 HGF/SF and menthol increase human glioblastoma cell calcium and migration. Biochemical and biophysical research communications 96 18485891
2004 HGF converts ErbB2/Neu epithelial morphogenesis to cell invasion. Molecular biology of the cell 95 15548598
1997 HGF/SF in angiogenesis. Ciba Foundation symposium 92 9524773
2018 HGF/MET and the Immune System: Relevance for Cancer Immunotherapy. International journal of molecular sciences 91 30441809
1993 Modulation of HGF-induced tubulogenesis and branching by multiple phosphorylation mechanisms. Developmental biology 89 8405677
2004 Therapeutic angiogenesis using hepatocyte growth factor (HGF). Current gene therapy 87 15180586
2006 HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB. Carcinogenesis 85 16840440
1997 Expression of HGF and cMet in the developing and adult brain. Brain research. Developmental brain research 84 9352114
2018 The Role of Hepatocyte Growth Factor (HGF) in Insulin Resistance and Diabetes. Frontiers in endocrinology 83 30214428
2008 HGF and MET mutations in primary and secondary lymphedema. Lymphatic research and biology 82 18564920
2018 HGF/c-MET Signaling in Melanocytes and Melanoma. International journal of molecular sciences 81 30513872
2009 Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. American journal of human genetics 81 19576567
1997 Control of invasive growth by hepatocyte growth factor (HGF) and related scatter factors. Cytokine & growth factor reviews 81 9244408
2008 Hepatocyte growth factor (HGF) and the satellite cell response following muscle lengthening contractions in humans. Muscle & nerve 77 18816607
2005 Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma. Blood 77 16189274
2003 EphA kinase activation regulates HGF-induced epithelial branching morphogenesis. The Journal of cell biology 77 14517207
1997 Role of HGF/SF and c-Met in morphogenesis and metastasis of epithelial cells. Ciba Foundation symposium 75 9524774
2014 HGF-Met Pathway in Regeneration and Drug Discovery. Biomedicines 74 28548072
1999 SF/HGF is a mediator between limb patterning and muscle development. Development (Cambridge, England) 69 10518504
2017 Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy. Experimental & molecular medicine 67 28336955
2000 Expression of Hepatocyte Growth Factor (HGF) and its Receptor (MET) in Medullary Carcinoma of the Thyroid. Endocrine pathology 67 12114654
1993 Roles of HGF as a pleiotropic factor in organ regeneration. EXS 66 8422545
2014 Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs. Cancer research 64 25217525
2000 Functional expression of HGF and its receptor in human colorectal cancer. Digestion 64 10878450
2020 Targeting HGF/c-MET Axis in Pancreatic Cancer. International journal of molecular sciences 63 33271944
2018 Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. The Journal of clinical investigation 61 29990309
1996 The HGF receptor family: unconventional signal transducers for invasive cell growth. Genes to cells : devoted to molecular & cellular mechanisms 61 9135079
2017 MET/HGF pathway activation as a paradigm of resistance to targeted therapies. Annals of translational medicine 60 28164089
2001 HGF- and KGF-induced activation of PI-3K/p70 s6 kinase pathway in corneal epithelial cells: its relevance in wound healing. Experimental eye research 60 11446769
2017 Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma. Cancers 59 28696366
2018 Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer. Cancers 57 30134579
2015 Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling. Nature communications 57 26239146
2008 HGF as a renotrophic and anti-fibrotic regulator in chronic renal disease. Frontiers in bioscience : a journal and virtual library 57 18508717
2005 The HGF receptor c-Met is overexpressed in esophageal adenocarcinoma. Neoplasia (New York, N.Y.) 54 15720819
1993 Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells. EXS 54 8380735
2013 HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma. The Journal of clinical investigation 53 23934123
2017 Targeting the HGF/c-MET pathway: stromal remodelling in pancreatic cancer. Oncotarget 51 29100344
1998 Coexpression of HGF and c-Met/HGF receptor in human bone and soft tissue tumors. Pathology international 49 9788258
2019 LC3C-Mediated Autophagy Selectively Regulates the Met RTK and HGF-Stimulated Migration and Invasion. Cell reports 47 31851933
2014 Genomic instability causes HGF gene activation in colon cancer cells, promoting their resistance to necroptosis. Gastroenterology 46 25244939
2003 Tyrosine kinase signal specificity: lessons from the HGF receptor. Trends in biochemical sciences 46 14559181
1993 Expression of the met-receptor and its ligand, HGF-SF during mouse embryogenesis. EXS 46 8380744
2016 The role of HGF/c-MET signaling pathway in lymphoma. Journal of hematology & oncology 45 27923392
2010 Quantitative analysis of HGF and EGF-dependent phosphotyrosine signaling networks. Journal of proteome research 45 20222723
2014 HGF/Met Axis in Heart Function and Cardioprotection. Biomedicines 44 28548070
1996 Primary structure of rat HGF receptor and induced expression in glomerular mesangial cells. The American journal of physiology 44 8853431
2016 Gene of the month: HGF. Journal of clinical pathology 42 27072686
2012 Role of HGF/MET axis in resistance of lung cancer to contemporary management. Translational lung cancer research 42 25806180
1999 Hepatocyte growth factor (HGF) as a potential index of severity of hypertension. Hypertension research : official journal of the Japanese Society of Hypertension 42 10515437
2012 Mechanisms of HGF/Met signaling to Brk and Sam68 in breast cancer progression. Hormones & cancer 41 22124844
2014 Physiological Signaling and Structure of the HGF Receptor MET. Biomedicines 40 28536396
2008 NK4 gene therapy targeting HGF-Met and angiogenesis. Frontiers in bioscience : a journal and virtual library 39 17981681
2002 MAP kinase and beta-catenin signaling in HGF induced RPE migration. Molecular vision 39 12500177
2022 HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET. Journal of experimental & clinical cancer research : CR 38 36109787
2013 HGF and c-Met interaction promotes migration in human chondrosarcoma cells. PloS one 38 23320110
2001 Met protein and hepatocyte growth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumourigenesis. The Journal of pathology 38 11329134
2011 Novel therapy for myocardial infarction: can HGF/Met be beneficial? Cellular and molecular life sciences : CMLS 37 21327916
2004 Electroporation-mediated HGF gene transfer ameliorated cyclosporine nephrotoxicity. Kidney international 37 15149317
1995 The Met-HGF/SF autocrine signaling mechanism is involved in sarcomagenesis. EXS 37 8527903
1993 Molecular characteristics of HGF-SF and its role in cell motility and invasion. EXS 37 8380739
2000 Inhibition of HGF/SF-induced breast cancer cell motility and invasion by the HGF/SF variant, NK4. Breast cancer research and treatment 36 10832594
1999 Hepatocyte growth factor (HGF) receptor expression and role of HGF during embryonic mouse testis development. Developmental biology 36 10588883
2009 PAK1 and PAK2 have different roles in HGF-induced morphological responses. Cellular signalling 35 19628037
2021 CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling. Theranostics 34 33500715
2020 HGF/MET Signaling in Malignant Brain Tumors. International journal of molecular sciences 34 33066121
2015 HGF mediated upregulation of lipocalin 2 regulates MMP9 through nuclear factor-κB activation. Oncology reports 34 26259977
2014 Developing biomarkers to predict benefit from HGF/MET pathway inhibitors. The Journal of pathology 34 24105670
2020 Neutrophilic HGF-MET Signalling Exacerbates Intestinal Inflammation. Journal of Crohn's & colitis 33 32556102
2020 Emodin Retarded Renal Fibrosis Through Regulating HGF and TGFβ-Smad Signaling Pathway. Drug design, development and therapy 33 32943844
2021 HGF/c-Met Signalling in the Tumor Microenvironment. Advances in experimental medicine and biology 31 33123991
2020 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. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 32152201
2011 HGF/c-MET targeted therapeutics: novel strategies for cancer medicine. Current drug targets 30 21777195
1999 Biological role of HGF/MET pathway in renal cell carcinoma. The Journal of urology 30 10022739
2009 Inhibition of HGF/MET as therapy for malignancy. Expert opinion on therapeutic targets 29 19397476
2008 HGF/MET signaling in ovarian cancer. Current molecular medicine 29 18781954
2021 The Role of HGF/MET Signaling in Metastatic Uveal Melanoma. Cancers 27 34771620
2010 Sulf1A and HGF regulate satellite-cell growth. Journal of cell science 27 20442248

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