Affinage

MET

Hepatocyte growth factor receptor · UniProt P08581

Round 2 corrected
Length
1390 aa
Mass
155.5 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MET is a receptor tyrosine kinase that serves as the sole high-affinity receptor for hepatocyte growth factor (HGF/scatter factor), transducing extracellular signals into programs of cell proliferation, survival, motility, invasion, and branching tubulogenesis (PMID:1846706, PMID:1655405, PMID:9440692). Ligand-induced dimerization triggers autophosphorylation at kinase-activating tyrosines Y1234/Y1235 and a bidentate multifunctional docking site (Y1349/Y1356) that recruits SH2-domain effectors including PI3K, PLCγ, SRC, GRB2/SOS, and STAT3, with STAT3 specifically required for tubulogenesis (PMID:7513258, PMID:8183564, PMID:9440692). Receptor downregulation depends on Cbl-mediated ubiquitination at juxtamembrane residue Y1003; somatic or germline mutations causing MET exon 14 skipping delete this domain, abolish Cbl-dependent turnover, and produce constitutive receptor accumulation that drives oncogenesis—including hereditary papillary renal carcinoma (activating kinase-domain mutations) and osteofibrous dysplasia (exon 14 splice-site mutations) (PMID:9140397, PMID:25971938, PMID:26637977). MET amplification confers resistance to EGFR inhibitors by activating an ERBB3/PI3K/AKT bypass pathway, and MET transcription is upregulated by HIF-1α under hypoxia and by PAX3/ETS1 in melanoma, establishing feed-forward circuits that amplify invasive growth signaling (PMID:17463250, PMID:12726861, PMID:25531327).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1986 High

    Identification of MET as a tyrosine kinase oncogene resolved the molecular basis of the transforming activity generated by chemical carcinogen treatment of a human osteosarcoma cell line, establishing the TPR-MET fusion as the activating event.

    Evidence Molecular cloning and NIH 3T3 transformation assay identified TPR-MET chromosomal translocation fusion

    PMID:2423252

    Open questions at the time
    • Full-length wild-type MET protein function unknown
    • Ligand identity unknown
    • Mechanism of kinase activation by fusion not determined
  2. 1991 High

    Demonstration that HGF and scatter factor are the same ligand and that c-MET is their receptor unified two fields and established the ligand–receptor pair governing motility, growth, and invasion.

    Evidence Radiolabeled HGF crosslinking, immunoprecipitation, and baculovirus-expressed MET binding assays by multiple independent groups

    PMID:1655405 PMID:1827664 PMID:1846706

    Open questions at the time
    • Downstream signaling effectors not yet mapped
    • Structural basis of ligand–receptor interaction unknown
    • Role of receptor dimerization not established
  3. 1994 High

    Mapping the multifunctional docking site and kinase-activating tyrosines defined the two-tier phosphorylation mechanism — Y1234/Y1235 for catalytic activation and Y1349/Y1356 for recruitment of PI3K, PLCγ, SRC, and GRB2 — explaining how a single receptor diversifies downstream signaling.

    Evidence Site-directed mutagenesis combined with co-immunoprecipitation, in vitro kinase assays, and transformation assays

    PMID:7513258 PMID:8183564

    Open questions at the time
    • STAT pathway contribution not yet established
    • Negative regulatory mechanisms unknown
    • Structural basis of multisubstrate docking not resolved
  4. 1998 High

    Discovery that STAT3 recruitment to MET is specifically required for tubulogenesis — but dispensable for scattering and growth — revealed how MET partitions distinct morphogenetic programs through selective effector engagement.

    Evidence Blocking peptides and decoy oligonucleotides against STAT3 selectively inhibited tubule formation in MDCK cells

    PMID:9440692

    Open questions at the time
    • Additional transcriptional targets of STAT3 in tubulogenesis not identified
    • Mechanism distinguishing STAT3-dependent versus -independent outputs unclear
  5. 1997 High

    Identification of germline MET kinase-domain mutations in hereditary papillary renal carcinoma families provided the first genetic proof that constitutive MET activation is sufficient to initiate human cancer.

    Evidence Genetic linkage analysis and sequencing of HPRC families identified activating missense mutations in the tyrosine kinase domain

    PMID:9140397

    Open questions at the time
    • Functional proof of constitutive kinase activity for each mutant not yet provided
    • Tissue specificity of tumorigenesis unexplained
  6. 2000 High

    Demonstration of selective MET–RON transphosphorylation established that MET signals extend beyond its own docking site through cross-activation of a subfamily-restricted partner receptor.

    Evidence Kinase-dead mutant co-expression, crosslinking, and co-immunoprecipitation showed reciprocal Met–Ron phosphorylation but no cross-talk with EGFR/HER2/TrkA

    PMID:10871856

    Open questions at the time
    • In vivo significance of Met–Ron cross-talk in normal physiology not demonstrated
    • Structural determinants of subfamily specificity not resolved
  7. 2003 High

    Discovery that hypoxia induces MET transcription via HIF-1α explained how the tumor microenvironment amplifies invasive growth signaling, linking oxygen sensing directly to receptor tyrosine kinase expression.

    Evidence Promoter-reporter assays, antisense inhibition, and xenograft hypoxia analysis

    PMID:12726861

    Open questions at the time
    • Quantitative relationship between hypoxia severity and MET upregulation not defined
    • Contribution of HIF-2α not assessed
  8. 2007 High

    The finding that MET amplification drives EGFR-inhibitor resistance through ERBB3/PI3K/AKT bypass signaling resolved a major clinical puzzle and established MET as a therapeutic co-target in EGFR-mutant lung cancer.

    Evidence Array CGH, FISH, siRNA knockdown, and kinase inhibitor sensitivity assays in resistant cell lines and patient specimens

    PMID:17463250 PMID:20129249

    Open questions at the time
    • Threshold of MET amplification required for bypass not defined
    • Whether HGF ligand-driven resistance uses identical or distinct downstream pathways fully resolved only later
  9. 2015 High

    Characterization of MET exon 14 skipping mutations unified receptor turnover biology with oncogenesis: loss of the juxtamembrane Cbl-binding domain abolishes ubiquitin-dependent degradation, causing surface receptor accumulation and constitutive signaling that is targetable by MET inhibitors. Germline exon 14 splice mutations also cause osteofibrous dysplasia, extending the phenotypic spectrum beyond cancer.

    Evidence Comprehensive genomic profiling of >38,000 tumors, in vitro functional models, MET inhibitor sensitivity assays, and OFD family genetic studies with osteoblast differentiation assays

    PMID:25971938 PMID:26637977

    Open questions at the time
    • Full spectrum of exon 14 splice-site variants and their penetrance not catalogued
    • Structural consequences of juxtamembrane domain loss on receptor conformation unknown
  10. 2016 High

    Elucidation of MET-to-EGFR transactivation via SRC/iRhom/ADAM17-dependent ligand shedding revealed a paracrine amplification loop relevant to squamous carcinogenesis, showing MET function extends beyond its canonical signaling cascade.

    Evidence Transgenic MT-HGF mouse model with pharmacological EGFR inhibition and pathway dissection in keratinocyte cultures

    PMID:27330189

    Open questions at the time
    • Relevance to human squamous cell carcinoma not directly demonstrated
    • Which specific EGFR ligand(s) are the primary mediators not fully resolved
  11. 2019 Medium

    Discovery that MET forms a phosphorylation-dependent complex with JAK2 and that MET inhibitors block IFNγ-induced PD-L1/PD-L2 upregulation connected MET signaling to immune evasion, providing a mechanistic rationale for combining MET and immune checkpoint therapies.

    Evidence Co-immunoprecipitation of MET/JAK2, PD-L1/PD-L2 expression analysis in cell lines and patient-derived organoids

    PMID:30723303

    Open questions at the time
    • In vivo immune microenvironment effects of MET inhibition on PD-L1 not validated in syngeneic models
    • Generalizability beyond MET-amplified tumors not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structural basis of HGF-induced MET dimerization and activation, the quantitative rules governing effector selectivity at the multifunctional docking site, and whether non-canonical MET products such as circMET-derived MET404 contribute to signaling in physiological contexts.
  • No full-length MET–HGF co-crystal structure
  • Quantitative kinetic model of docking-site effector competition absent
  • CircMET/MET404 mechanism from single lab, not independently replicated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2
Partners
CBLERBB3GRB2HGFJAK2RONSTAT3VEGFR2
Complex memberships
MET-RON heterocomplexMET-VEGFR2-PTP1B complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 The MET oncogene was activated in vitro by chromosomal translocation fusing 5' sequences of the TPR locus (chromosome 1) with the MET proto-oncogene (chromosome 7q21-31), generating a novel 5.0 kb hybrid transcript (TPR-MET) and identifying MET as a member of the tyrosine kinase gene family. Molecular cloning, Northern blot, NIH 3T3 transformation assay Cell High 2423252
1987 The MET proto-oncogene cDNA encodes a 1408-amino-acid protein with a signal peptide, a hydrophobic transmembrane segment defining an extracellular domain of 926 amino acids, and an intracellular tyrosine kinase domain most homologous to the insulin receptor and v-abl, establishing MET as a receptor tyrosine kinase. cDNA sequencing and structural analysis Proceedings of the National Academy of Sciences of the United States of America High 2819873
1991 The c-MET proto-oncogene product was identified as the cell-surface receptor for hepatocyte growth factor (HGF): HGF treatment of cells overexpressing c-MET induced tyrosine phosphorylation of the p190c-met beta subunit, and covalent crosslinking of 125I-labeled HGF directly established c-met as the HGF receptor. Immunoblot, in vitro kinase assay, covalent crosslinking of radiolabeled ligand, immunoprecipitation Science / Oncogene High 1827664 1846706
1991 Scatter Factor (SF) and HGF are indistinguishable ligands that bind the same receptor (MET/c-met product) with identical affinities, induce equivalent biological responses (growth, motility, invasion), and activate ligand-induced tyrosine phosphorylation of the Met beta subunit; binding activity was confirmed by baculovirus expression of MET cDNA in insect cells. Ligand binding, crosslinking, immunoprecipitation, baculovirus expression, biological activity assays The EMBO Journal High 1655405
1994 The HGF/SF receptor (MET) contains a multifunctional docking site composed of tandemly arranged degenerate bidentate motif YVH/NV; phosphorylation of this site mediates intermediate- to high-affinity interactions with multiple SH2-containing signal transducers including PI3K, PLCγ, pp60c-src, and GRB-2/Sos complex. Mutation of both tyrosines abrogates transforming activity of the oncogenic form. Mutagenesis, co-immunoprecipitation, in vitro binding assays, transformation assay Cell High 7513258
1994 Structural and functional analysis of MET constructs showed that: (1) the truncated cytoplasmic domain of HGF receptor has constitutive tyrosine kinase activity and is oncogenic; (2) the first 39 amino acids of the juxtamembrane domain are required to unleash transforming potential; (3) tyrosine residues Y1234 and Y1235 in the kinase domain are required for positive regulation of catalytic activity and transforming potential. Mutagenesis, in vitro kinase assay, NIH 3T3 transformation assay, nude mouse tumorigenicity assay Oncogene High 8183564
1996 Ets transcription factors (specifically ETS1) directly activate MET transcription: the 300-bp proximal MET promoter contains Ets consensus binding sites; co-expression of ETS1 strongly enhanced MET promoter activity; decoy oligonucleotides blocked Ets binding and reduced Met protein levels. Additionally, Met activation induces ETS1 mRNA, creating a positive feedback loop. Promoter deletion analysis, transient co-transfection, stable transfection, decoy oligonucleotide competition, Western blot Oncogene High 8934537
1997 Autocrine co-expression of Met and HGF/SF in mouse fibroblasts results in transformation, tumorigenesis, invasion, and metastasis. Met-HGF/SF signaling activates the urokinase plasminogen proteolysis network, coupling Met signal transduction to extracellular matrix dissolution required for branching morphogenesis and invasion. Autocrine cell line construction, in vitro invasion assay, in vivo tumorigenicity in nude mice, biochemical pathway analysis Ciba Foundation symposium Medium 9524767
1997 Germline missense mutations in the tyrosine kinase domain of MET are causally associated with hereditary papillary renal carcinoma (HPRC), with mutations at codons homologous to activating mutations in c-kit and RET, suggesting constitutive activation of MET kinase activity drives renal tumorigenesis. Genetic linkage analysis, DNA sequencing of germline and somatic samples, identification of activating mutations in tyrosine kinase domain Nature genetics High 9140397
1998 HGF-induced tubulogenesis (the third phase of the morphogenetic program) depends specifically on the STAT pathway: HGF stimulates Stat-3 recruitment to the MET receptor, tyrosine phosphorylation, nuclear translocation, and binding to the SIE promoter element. Blocking STAT association with the receptor or STAT DNA binding inhibits tubule formation without affecting scattering or growth. Biochemical fractionation, electroporation of blocking peptides, decoy oligonucleotides, reporter assays Nature High 9440692
2000 MET and RON receptors form non-covalent complexes on the cell surface before ligand-induced dimerization and undergo ligand-induced transphosphorylation: activated Met phosphorylates Ron at both kinase-activating tyrosines (Y1238/Y1239) and docking tyrosines (Y1353/Y1360), and vice versa. This cross-talk is specific to the scatter factor receptor subfamily and does not occur between Met/Ron and ErbB1, ErbB2, or TrkA. Kinase-inactive Ron suppresses transformation by oncogenic Met mutants. Kinase-inactive mutant co-expression, crosslinking, co-immunoprecipitation, transformation assay Oncogene High 10871856
2003 Hypoxia activates transcription of the MET proto-oncogene via HIF-1α binding to the MET promoter, resulting in elevated Met protein levels, amplified HGF signaling, and synergistic promotion of invasive growth. Inhibition of Met expression prevents hypoxia-induced invasion. Promoter-reporter assays, Western blot, invasion assay, tumor xenograft hypoxia analysis, antisense inhibition Cancer cell High 12726861
2004 Met receptor downregulation requires ubiquitination through the E3 ligase Cbl, and this ubiquitination is required for receptor degradation via an endocytic mechanism that also requires proteasome activity. Perturbation of Met trafficking at internalization or early endosomal sorting alters signaling outputs. A Met mutant defective in Cbl binding is able to transform cells. Endocytic trafficking assays, ubiquitination assays, proteasome inhibition, Cbl-binding mutant analysis Current topics in microbiology and immunology Medium 15645709
2007 MET amplification causes acquired resistance to the EGFR kinase inhibitor gefitinib by driving ERBB3 (HER3)-dependent activation of PI3K, bypassing EGFR inhibition. Inhibition of MET signaling in MET-amplified resistant cells restored sensitivity to gefitinib. MET amplification was detected in 22% of lung cancer specimens with acquired resistance to gefitinib or erlotinib. Array CGH, FISH, kinase inhibitor sensitivity assays, PI3K pathway analysis, siRNA knockdown Science High 17463250
2008 MicroRNAs miR-34b, miR-34c, and miR-199a* negatively regulate MET expression at the translational level. Inhibition of these endogenous miRNAs by antagomiRs increased MET protein; exogenous expression in cancer cells blocked MET-induced signal transduction and the invasive growth program in cells expressing normal or constitutively active MET. AntagomiR transfection, miRNA overexpression, Western blot, invasion assay, signal transduction analysis Cancer research Medium 19074879
2010 Pre-existing subpopulations of cells with MET amplification are present before drug exposure in EGFR-mutant lung cancers; these are clonally selected by EGFR inhibitor treatment. MET amplification activates ERBB3/PI3K/AKT signaling, while HGF-induced MET activation causes resistance through GAB1 signaling. Combined EGFR and MET inhibition cured resistance in vivo. High-throughput FISH, in vitro drug resistance modeling, signaling pathway analysis, in vivo combination therapy Cancer cell High 20129249
2011 In MET-amplified/addicted cancer cells, activated Met specifically transphosphorylates Ron kinase but not other RTKs (EGFR, HER2). Ron phosphorylation is suppressed by Met-specific kinase inhibitors and by antibody-induced Met shedding. shRNA silencing of RON in MET-addicted cells decreased proliferation, clonogenic activity in vitro, and tumorigenicity in vivo, establishing Ron transactivation as a component of MET oncogene addiction. shRNA silencing, kinase inhibitors, Met-shedding antibody, clonogenic assay, xenograft tumorigenicity Cancer research High 21212418
2012 Melanoma-derived exosomes transfer the MET oncoprotein to bone marrow progenitor cells, educating them toward a pro-metastatic, pro-vasculogenic phenotype (c-Kit+/Tie2+/Met+). Reducing Met expression in exosomes diminished pro-metastatic bone marrow cell behavior, and Rab27A knockdown decreased exosome production and blocked bone marrow education. Exosome isolation, receptor expression analysis (flow cytometry), Met knockdown, in vivo metastasis models, Rab27A RNAi Nature medicine High 22635005
2012 VEGF directly and negatively regulates tumor cell invasion by enhancing recruitment of protein tyrosine phosphatase PTP1B to a MET/VEGFR2 heterocomplex, suppressing HGF-dependent MET phosphorylation and tumor cell migration. VEGF blockade restores MET activity in glioblastoma cells independent of hypoxia and induces EMT with a T-cadherin to N-cadherin switch. Co-immunoprecipitation of MET/VEGFR2 complex, PTP1B recruitment assay, migration assay, in vivo GBM models with MET inhibition Cancer cell High 22789536
2014 PAX3 and ETS1 transcription factors directly interact and synergistically activate MET transcription in melanoma cells. PAX3 and ETS1 bind distinct elements within the 300-bp proximal MET promoter; PAX3 knockdown reduces MET receptor levels. Additionally, HGF-dependent ETS1 activation further enhances MET expression, creating an indirect positive feedback loop by which MET promotes its own transcription. Promoter reporter assay, ChIP, co-immunoprecipitation, PAX3/ETS1 knockdown, in vitro and in vivo growth assays Oncogene High 25531327
2014 USP8 is a LRIG1-specific deubiquitinating enzyme that regulates LRIG1 stability and, consequently, Met degradation. Anti-Met antibody SAIT301 induces ubiquitination of LRIG1, which promotes recruitment of the Met/LRIG1 complex to lysosomes via Hrs interaction and concomitant degradation of both proteins. Inhibiting USP8-LRIG1 interaction by SAIT301 triggers LRIG1 ubiquitination and Met degradation without Met activation. Co-immunoprecipitation, ubiquitination assay, lysosomal trafficking assay, USP8 overexpression/knockdown, Western blot Scientific reports Medium 24828152
2015 Recurrent somatic splice site alterations at MET exon 14 (METex14) result in exon skipping, loss of the juxtamembrane domain (which contains the Cbl E3 ubiquitin ligase binding site Y1003 and regulatory sequences), constitutive MET receptor activation, and oncogenic transformation in vitro. These alterations confer clinical sensitivity to MET inhibitors. Comprehensive genomic profiling of 38,028 patient tumors, in vitro functional studies with METex14 cell models, MET inhibitor sensitivity assays Cancer discovery High 25971938
2015 MET exon 14 skipping mutations remove the juxtamembrane domain, which contains the negative regulatory sequences for Cbl-mediated ubiquitination (Y1003) and receptor turnover, leading to receptor accumulation on the cell surface and prolonged HGF-induced activation; the resulting receptor retains HGF affinity but lacks negative regulatory function. Molecular analysis of splice variants, functional studies in cell lines, MET inhibitor sensitivity assays Cancer treatment reviews / Journal of thoracic oncology Medium 32334240
2015 Germline mutations in MET preventing regulated exon 14 skipping cause osteofibrous dysplasia (OFD). Loss of juxtamembrane domain encoded by exon 14 (MET-Δ14) stabilizes the mature MET protein and retards osteoblastic differentiation in vitro; forced exon 14 exclusion inhibits bone matrix mineralization. A somatic OFD mutation also affecting exon 14 substitutes a tyrosine critical for MET receptor turnover, similarly stabilizing the protein. Genetic linkage in OFD families, in vitro osteoblast differentiation assay, splice variant analysis, protein stability assays American journal of human genetics High 26637977
2015 Artificial dimeric macrocyclic peptides identified via the RaPID system specifically activate Met by inducing receptor dimerization, mimicking HGF. These Met-activating dimeric macrocycles stimulate downstream Akt and Erk signaling and induce branching morphogenesis in human cells. RaPID selection, macrocycle dimerization design, receptor dimerization assay, downstream kinase activation, branching morphogenesis assay Nature communications Medium 25758345
2016 MET signaling in keratinocytes activates EGFR to initiate squamous carcinogenesis: HGF/MET signaling increases synthesis and release of EGFR ligands through SRC, iRhom1/iRhom2, and ADAM17, leading to autocrine EGFR activation. EGFR inhibition caused regression of MET-driven squamous tumors. Transgenic MT-HGF mouse model, pharmacological inhibition, gene expression profiling, keratinocyte culture with signaling analysis Science signaling High 27330189
2019 In MET-amplified tumors, MET inhibition counteracts IFNγ-induced upregulation of PD-L1 and PD-L2. JAK2 associates with MET in the same signaling complex in a MET phosphorylation-dependent manner; MET inhibitors neutralize JAK/STAT1 signaling downstream of the IFNγ receptor, thereby preventing PD-1 ligand induction. Co-immunoprecipitation of MET/JAK2 complex, PD-L1/PD-L2 expression analysis, MET inhibitor treatment in cell lines and patient-derived organoids, STAT1 phosphorylation assay British journal of cancer Medium 30723303
2021 ENO1 (α-enolase) interacts directly with the HGF receptor (MET/HGFR) and activates HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt co-receptor LRP5/6, leading to GSK3β inactivation through Src-PI3K-AKT signaling, stabilization of β-catenin, and upregulation of the EMT regulator SLUG. Co-immunoprecipitation of ENO1-HGFR, phosphorylation assays, knockdown/overexpression, orthotopic and tail-vein metastasis models, anti-ENO1 antibody treatment Cancer research Medium 34145039
2021 CYP1A2 antagonizes HGF/MET signaling by directly binding HIF-1α (identified as a transcriptional activator of MET), inducing ubiquitin-mediated HIF-1α degradation and thereby inhibiting HIF-1α-mediated MET transcription. CYP1A2 overexpression also decreased HGF levels in HCC cells. Co-immunoprecipitation of CYP1A2-HIF-1α, ubiquitination assay, Western blot, in vitro and in vivo HCC models Theranostics Medium 33500715
2023 Circular MET RNA (circMET) encodes a 404-amino-acid MET variant (MET404) translated via m6A/YTHDF2-facilitated mechanism. MET404 directly interacts with the MET β subunit to form a constitutively active MET receptor complex that does not require HGF stimulation. Genetic ablation of circMET inhibits MET404 expression and attenuates MET signaling; MET404 knock-in plus p53 knockout in mouse astrocytes initiates GBM tumorigenesis. CircRNA identification and sequencing, m6A/YTHDF2 reader assay, MET404-MET β subunit co-immunoprecipitation, genetic knock-in/knock-out mouse model, neutralizing antibody, in vitro and in vivo tumorigenesis assays Nature communications Medium 37491377

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, N.Y.) 3855 17463250
2012 Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature medicine 3008 22635005
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
1991 Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science (New York, N.Y.) 2191 1846706
2013 Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 2076 23470965
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2007 MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the National Academy of Sciences of the United States of America 1417 18093943
1997 Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nature genetics 1256 9140397
2012 Targeting MET in cancer: rationale and progress. Nature reviews. Cancer 1212 22270953
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2003 Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer cell 1093 12726861
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1994 A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 896 7513258
2010 Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer cell 886 20129249
1994 Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav. Molecular and cellular biology 840 7511210
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2020 EMT, MET, Plasticity, and Tumor Metastasis. Trends in cell biology 777 32800658
1991 Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET. Oncogene 740 1827664
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2007 Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 659 17981115
1991 Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. The EMBO journal 659 1655405
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2015 Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer discovery 640 25971938
1987 Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proceedings of the National Academy of Sciences of the United States of America 575 2819873
2011 Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer cell 572 22137795
2016 MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 560 26729443
1986 Mechanism of met oncogene activation. Cell 535 2423252
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2009 Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 490 19255323
2012 VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer cell 465 22789536
1998 Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 451 9440692
2013 EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 450 24034250
2008 Signaling networks assembled by oncogenic EGFR and c-Met. Proceedings of the National Academy of Sciences of the United States of America 447 18180459
2016 Targeting MET in Lung Cancer: Will Expectations Finally Be MET? Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 301 27794501
2008 Expression and mutational analysis of MET in human solid cancers. Genes, chromosomes & cancer 268 18709663
2012 TFIIH: when transcription met DNA repair. Nature reviews. Molecular cell biology 247 22572993
1996 Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. The American journal of pathology 219 8546209
2003 How to make tubes: signaling by the Met receptor tyrosine kinase. Trends in cell biology 203 12791299
2020 Targeting MET Dysregulation in Cancer. Cancer discovery 185 32532746
2009 Crosstalk in Met receptor oncogenesis. Trends in cell biology 174 19758803
2013 The emerging role of MET/HGF inhibitors in oncology. Cancer treatment reviews 160 23453860
2000 Cross-talk between the proto-oncogenes Met and Ron. Oncogene 159 10871856
2008 MicroRNAs impair MET-mediated invasive growth. Cancer research 150 19074879
2017 Targeting MET in cancer therapy. Chronic diseases and translational medicine 149 29063069
2007 From Tpr-Met to Met, tumorigenesis and tubes. Oncogene 143 17322912
2015 Activating MET kinase rearrangements in melanoma and Spitz tumours. Nature communications 133 26013381
2015 When plant virology met Agrobacterium: the rise of the deconstructed clones. Plant biotechnology journal 123 26073158
2019 MET in glioma: signaling pathways and targeted therapies. Journal of experimental & clinical cancer research : CR 120 31221203
2021 ENO1 Promotes Lung Cancer Metastasis via HGFR and WNT Signaling-Driven Epithelial-to-Mesenchymal Transition. Cancer research 118 34145039
1996 Ets up-regulates MET transcription. Oncogene 118 8934537
1997 Met-HGF/SF: tumorigenesis, invasion and metastasis. Ciba Foundation symposium 115 9524767
2009 Colon cancer metastasis: MACC1 and Met as metastatic pacemakers. The international journal of biochemistry & cell biology 112 19666136
2016 ABBV-399, a c-Met Antibody-Drug Conjugate that Targets Both MET-Amplified and c-Met-Overexpressing Tumors, Irrespective of MET Pathway Dependence. Clinical cancer research : an official journal of the American Association for Cancer Research 111 27573171
2006 Initiation of protein synthesis by hepatitis C virus is refractory to reduced eIF2.GTP.Met-tRNA(i)(Met) ternary complex availability. Molecular biology of the cell 109 16928960
2008 Molecular cancer therapy: can our expectation be MET? European journal of cancer (Oxford, England : 1990) 106 18295476
2020 Reversible EMT and MET mediate amnion remodeling during pregnancy and labor. Science signaling 98 32047115
2021 HGF and MET: From Brain Development to Neurological Disorders. Frontiers in cell and developmental biology 94 34179015
2015 Artificial human Met agonists based on macrocycle scaffolds. Nature communications 89 25758345
1996 Expression of Met protein in thyroid tumours. The Journal of pathology 86 8958803
2008 HGF and MET mutations in primary and secondary lymphedema. Lymphatic research and biology 81 18564920
2021 The role of MET in chemotherapy resistance. Oncogene 80 33526881
2018 Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 80 30069760
2017 Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients. Clinical cancer research : an official journal of the American Association for Cancer Research 75 29284707
2016 AKT-ions with a TWIST between EMT and MET. Oncotarget 74 27623213
2020 Alterations in the PI3K Pathway Drive Resistance to MET Inhibitors in NSCLC Harboring MET Exon 14 Skipping Mutations. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 72 32169477
1994 Structural and functional domains critical for constitutive activation of the HGF-receptor (Met). Oncogene 70 8183564
2020 The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping. Cancer treatment reviews 66 32334240
2013 Targeting hepatocyte growth factor receptor (Met) positive tumor cells using internalizing nanobody-decorated albumin nanoparticles. Biomaterials 65 24139763
2015 Hepatocyte growth factor and Met in drug discovery. Journal of biochemistry 64 25770121
2011 Ron kinase transphosphorylation sustains MET oncogene addiction. Cancer research 63 21212418
2016 Regulation of the MET oncogene: molecular mechanisms. Carcinogenesis 59 26905592
2009 Targeting the Met signaling pathway in renal cancer. Expert review of anticancer therapy 59 19496715
2015 Gastrointestinal malignancies harbor actionable MET exon 14 deletions. Oncotarget 56 26375439
2010 MET molecular mechanisms and therapies in lung cancer. Cell adhesion & migration 55 20139696
2023 Circular RNA encoded MET variant promotes glioblastoma tumorigenesis. Nature communications 54 37491377
2020 MET Exon 14-altered Lung Cancers and MET Inhibitor Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 53 33172896
2010 When fibroblasts MET iPSCs. Cell stem cell 53 20621040
2020 MET targeting: time for a rematch. Oncogene 50 32034310
2021 MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors. Experimental hematology & oncology 48 34758872
2010 Targeting the MET oncogene in cancer and metastases. Expert opinion on investigational drugs 48 20868306
2021 Roles of MET in human cancer. Clinica chimica acta; international journal of clinical chemistry 46 34951962
2015 C-MET overexpression and amplification in gliomas. International journal of clinical and experimental pathology 46 26823824
2022 The limits of human microRNA annotation have been met. RNA (New York, N.Y.) 43 35236776
2015 Gene of the month: MET. Journal of clinical pathology 43 25987653
1995 Amplification of the MET gene in glioma. Genes, chromosomes & cancer 42 7534113
2011 Activating mutation in MET oncogene in familial colorectal cancer. BMC cancer 40 21970370
2019 Met inhibition revokes IFNγ-induction of PD-1 ligands in MET-amplified tumours. British journal of cancer 39 30723303
2018 Have Clinical Trials Properly Assessed c-Met Inhibitors? Trends in cancer 39 29458966
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