Affinage

MET

Hepatocyte growth factor receptor · UniProt P08581

Length
1390 aa
Mass
155.5 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: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MET encodes a heterodimeric (α-β) receptor tyrosine kinase whose activation drives proliferation, motility, invasion, and epithelial tubulogenesis, and which is a recurrent oncogenic driver across multiple cancers (PMID:2541345, PMID:12791299). Originally identified through a carcinogen-induced chromosomal translocation fusing the TPR locus to MET to generate the constitutively active Tpr-Met oncogene (PMID:2423252), the receptor is a p190 complex of a 50 kDa α chain disulfide-linked to a 145 kDa β chain with intrinsic tyrosine kinase activity that is amplified and constitutively phosphorylated in tumor cells (PMID:2541345). Upon activation MET autophosphorylates and uses its C-terminal multisubstrate docking site to recruit Grb2, Gab1, SHP2, STAT3, Shc, SHIP-1, and Src, engaging PI3K, PLCγ, Src, and the ERK/MAP kinase cascade to sustain morphogenesis and survival signaling (PMID:8380734, PMID:12791299, PMID:16132696). Receptor output is normally limited by Cbl-mediated ubiquitination and lysosomal degradation; oncogenic activation circumvents this control, with exon 14 skipping deleting the juxtamembrane Cbl-binding negative regulatory domain to prolong signaling, and kinase-activating mutants redirected to GGA3-dependent endosomal recycling that enhances signaling (PMID:15645709, PMID:21917713, PMID:25971938, PMID:32334240). Diverse oncogenic activation modes converge on this kinase, including MET amplification, METex14 skipping, kinase-domain fusions (TRIM4-MET, ZKSCAN1-MET, PTPRZ1-MET) that constitutively fire MAPK/PI3K/PLCγ1, and a circRNA-encoded MET404 variant that binds the MET β subunit to assemble an HGF-independent active receptor (PMID:25971938, PMID:26013381, PMID:25935522, PMID:37491377). MET transcription is driven by Ets1, PAX3, and SOX10 through the proximal promoter, and is restrained post-transcriptionally by miR-34b/c and miR-199a* (PMID:8934537, PMID:19074879, PMID:20067553, PMID:25531327). The receptor cross-talks with other signaling systems, transphosphorylating Ron in MET-addicted cells, complexing with JAK2 to control IFN-γ-induced PD-L1/PD-L2 induction, and transactivating EGFR via SRC/iRhom/ADAM17-mediated ligand shedding; binding partners ENO1 and EpCAM (EpEX) further amplify MET signaling toward β-catenin-driven EMT and metastasis (PMID:21212418, PMID:27330189, PMID:30723303, PMID:34145039, PMID:37543570). Beyond cancer, MET function extends to auditory development, where a missense mutation causes autosomal recessive non-syndromic hearing loss (DFNB97), and to neutrophil-driven intestinal inflammation through IL-1β-mediated TH17 expansion (PMID:25941349, PMID:32556102). Acquired resistance to MET inhibitors arises through MET amplification and subsequent KRAS amplification that shifts cells to KRAS dependence (PMID:20841479).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1986 High

    Established that MET can be activated as an oncogene, defining the first mechanism by which a chromosomal rearrangement creates a constitutively active MET kinase.

    Evidence Southern blotting, chromosomal mapping, and NIH 3T3 transformation of carcinogen-treated HOS cells generating the Tpr-Met fusion

    PMID:2423252

    Open questions at the time
    • Did not characterize the normal receptor structure or ligand
    • Frequency of TPR-MET in spontaneous human tumors not addressed
  2. 1989 High

    Defined MET as a heterodimeric α-β receptor tyrosine kinase and linked gene amplification to constitutive kinase activity in tumor cells.

    Evidence Anti-phosphotyrosine IP, non-reducing SDS-PAGE, and amplification analysis in the GTL-16 gastric line

    PMID:2541345

    Open questions at the time
    • Downstream substrates not yet mapped
    • Ligand-dependent activation not characterized
  3. 1993 Medium

    Mapped the immediate signaling output of HGF-activated MET, identifying the effectors that transduce the receptor's mitogenic and motogenic signals.

    Evidence In vitro kinase assays and phosphotyrosine IP showing rapid PI3K, GAP, PLCγ, Src, and MAPK engagement

    PMID:8380734

    Open questions at the time
    • Direct vs adaptor-mediated recruitment not resolved
    • Single-lab biochemistry
  4. 1996 High

    Showed how MET expression is transcriptionally driven, identifying Ets1 as a promoter-binding activator in a positive feedback loop with MET signaling.

    Evidence MET promoter deletion, reporter co-transfection, stable Ets1 overexpression, and decoy oligonucleotides

    PMID:8934537

    Open questions at the time
    • Tissue specificity of Ets1 control unclear
    • Cooperating factors not yet defined
  5. 2003 Medium

    Connected MET signaling to epithelial tubulogenesis through the Gab1/SHP2 module required for sustained ERK activation.

    Evidence Review synthesizing 3D branching morphogenesis assays and dominant-negative epistasis

    PMID:12791299

    Open questions at the time
    • Review-level synthesis rather than single primary dataset
    • Quantitative contribution of each effector to morphogenesis not parsed
  6. 2004 Medium

    Established Cbl-mediated ubiquitination and lysosomal degradation as the negative control on MET, and linked its loss to transformation.

    Evidence Endocytic trafficking, ubiquitination assays, and Cbl-binding-defective mutant transformation assays

    PMID:15645709

    Open questions at the time
    • Endosomal signaling output not quantified here
    • Recycling fate of escapee receptors not yet defined
  7. 2005 Medium

    Defined the C-terminal multisubstrate docking site structurally and as the hub recruiting the adaptor/effector ensemble.

    Evidence Crystal structure of the MET kinase domain with domain-interaction analysis (review)

    PMID:16132696

    Open questions at the time
    • Structural source synthesized in a review
    • Phosphosite-specific binding stoichiometry not mapped
  8. 2008 High

    Identified post-transcriptional restraint of MET, showing specific miRNAs limit receptor levels and the invasive growth program.

    Evidence AntagomiR knockdown and miRNA overexpression with migration and signaling readouts in cancer/melanoma cells

    PMID:19074879

    Open questions at the time
    • Endogenous miRNA dosage in tumors not established
    • Other 3'UTR regulators not surveyed
  9. 2010 High

    Defined a clinically relevant resistance mechanism to MET inhibitors, showing oncogene switching from MET to KRAS.

    Evidence In vitro selection with two MET inhibitors across lines, copy-number and phosphorylation analysis

    PMID:20841479

    Open questions at the time
    • Whether KRAS bypass occurs in patients not tested here
    • Other bypass routes not enumerated
  10. 2010 Medium

    Extended transcriptional control of MET to the melanocyte lineage, defining PAX3/SOX10/MITF cooperation at the promoter.

    Evidence Promoter binding, reporter, co-transfection, and ChIP in melanoma cells

    PMID:20067553

    Open questions at the time
    • Relative contribution of direct vs MITF-indirect routes not quantified
    • Single-lab
  11. 2011 Medium

    Showed how activating mutants evade degradation by GGA3/Arf6/Crk-mediated endosomal recycling, linking trafficking to oncogenic signaling.

    Evidence Endocytic trafficking and recycling assays with adaptor-interaction studies

    PMID:21917713

    Open questions at the time
    • Synthesized as a perspective
    • Endosomal signaling effectors not fully defined
  12. 2011 High

    Established MET-driven transphosphorylation of Ron as a functional cross-talk required for the malignant phenotype in MET-addicted cells.

    Evidence Co-IP, kinase inhibitors, antibody-induced shedding, RON shRNA, and in vivo tumorigenicity

    PMID:21212418

    Open questions at the time
    • Stoichiometry of MET-Ron complex not defined
    • Generality beyond MET-addicted lines unclear
  13. 2011 Medium

    Provided structural insight into MET dimerization via the bacterial ligand InlB, with inferred parallels to HGF/SF activation.

    Evidence X-ray crystallography of MET-InlB complex and structural comparison

    PMID:21242015

    Open questions at the time
    • Parallels to physiological HGF activation inferred, not directly shown
    • HGF-bound dimer geometry not resolved here
  14. 2014 High

    Showed direct PAX3-ETS1 protein interaction and synergy at the proximal MET promoter, integrating two transcriptional inputs into a feedback loop with functional tumor relevance.

    Evidence Reporter assays, Co-IP, ChIP, siRNA, dominant-negative ETS1, and in vivo tumor growth

    PMID:25531327

    Open questions at the time
    • Promoter architecture in non-melanoma contexts not tested
    • Chromatin state dependence not addressed
  15. 2015 High

    Defined METex14 skipping as a recurrent activating event that deletes the juxtamembrane Cbl-binding regulatory domain and confers inhibitor sensitivity.

    Evidence Genomic profiling of 38,028 tumors with functional in vitro transformation and inhibitor assays

    PMID:25971938

    Open questions at the time
    • Quantitative degradation defect not directly measured here
    • Tissue-specific frequency drivers unclear
  16. 2015 Medium

    Established MET kinase-domain fusions as constitutive activators of MAPK/PI3K/PLCγ1 amenable to MET inhibition.

    Evidence Genomic identification and functional signaling/inhibitor characterization of TRIM4-MET and ZKSCAN1-MET

    PMID:26013381

    Open questions at the time
    • Single study
    • In vivo tumorigenicity of these fusions not shown
  17. 2015 Medium

    Characterized PTPRZ1-MET fusion processing and HGF-independent activation, broadening the fusion-driven activation repertoire.

    Evidence Western blotting, phosphorylation, dimerization, and mRNA analysis in ZM-carrying samples/models

    PMID:25935522

    Open questions at the time
    • Single-lab
    • Downstream pathway selectivity not mapped
  18. 2015 Medium

    Linked MET to a Mendelian phenotype, identifying a causal missense mutation in autosomal recessive non-syndromic hearing loss (DFNB97).

    Evidence Homozygosity mapping, whole-exome sequencing, Sanger confirmation, and cosegregation in a family

    PMID:25941349

    Open questions at the time
    • Functional consequence of p.F841V validated only by prediction
    • Mechanism in auditory development not established
  19. 2016 High

    Defined MET-to-EGFR transactivation via SRC/iRhom/ADAM17-mediated ligand shedding, revealing a therapeutically exploitable cross-talk in MET-driven tumors.

    Evidence MT-HGF transgenic mice, keratinocyte cultures, and pharmacological EGFR/SRC/ADAM17 inhibition with tumor regression

    PMID:27330189

    Open questions at the time
    • Generality across epithelial tissues not established
    • Relative weight of autocrine EGFR ligands not parsed
  20. 2019 High

    Established a physical MET-JAK2 complex controlling IFN-γ-induced PD-L1/PD-L2, linking MET to immune-evasion signaling.

    Evidence Reciprocal Co-IP, MET inhibitors, and PD-ligand analysis in MET-amplified lines and patient-derived organoids

    PMID:30723303

    Open questions at the time
    • In vivo immune consequences not directly tested
    • Direct vs indirect MET-JAK2 contact unresolved
  21. 2021 High

    Identified ENO1 as a direct MET-activating partner driving Wnt/β-catenin-dependent EMT and metastasis.

    Evidence Co-IP, knockdown/overexpression, anti-ENO1 antibody, and in vivo orthotopic/tail-vein models

    PMID:34145039

    Open questions at the time
    • Structural basis of ENO1-MET binding unknown
    • Generality beyond lung cancer untested
  22. 2021 High

    Established a non-cancer in vivo role for MET in neutrophils, promoting intestinal inflammation through IL-1β-driven TH17 expansion.

    Evidence MRP8-Cre MET-LoxP conditional knockout in DSS colitis with flow cytometry and cytokine readouts

    PMID:32556102

    Open questions at the time
    • Molecular link from MET to IL-1β not detailed
    • Relevance to human IBD not established
  23. 2021 Medium

    Defined CYP1A2 as an upstream suppressor of MET transcription by degrading HIF-1α, revealing a metabolic regulator of HGF/MET output.

    Evidence Co-IP, ubiquitination assays, CYP1A2 gain/loss-of-function, and in vivo tumor model

    PMID:33500715

    Open questions at the time
    • Single-lab
    • HIF-1α-independent effects on HGF not dissected
  24. 2023 High

    Showed that a circRNA-encoded MET404 variant assembles an HGF-independent active receptor, defining a non-canonical mode of constitutive MET activation in gliomagenesis.

    Evidence circMET ablation and MET404 knock-in mice, MET404-MET β Co-IP, neutralizing antibody, and tumorigenicity assays with YTHDF2 studies

    PMID:37491377

    Open questions at the time
    • Frequency of MET404 across tumor types unknown
    • Structural basis of MET404-β subunit activation not resolved
  25. 2023 High

    Identified EpCAM ectodomain (EpEX) as a direct MET ligand-like partner cooperating with HGF to drive EMT and metastasis.

    Evidence Co-IP, ELISA, FRET, downstream signaling Westerns, and in vivo metastasis models

    PMID:37543570

    Open questions at the time
    • Binding interface not mapped
    • Relative contribution of EpEX vs HGF in vivo not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse activation modes (amplification, METex14, fusions, MET404, non-HGF partners) differentially shape receptor trafficking, effector wiring, and therapeutic vulnerability remains incompletely resolved.
  • No unified structural model linking each activation mode to downstream signaling bias
  • Cross-talk hierarchy among Ron, EGFR, JAK2, ENO1, and EpCAM in vivo unestablished
  • Predictive biomarkers for bypass resistance beyond KRAS not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0060089 molecular transducer activity 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ENO1EPCAMGAB1GRB2HGFJAK2RONSHP2

Evidence

Reading pass · 26 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 the TPR (translocated promoter region) locus on chromosome 1 to the MET proto-oncogene locus on chromosome 7q21-31, generating a hybrid 5.0 kb transcript (Tpr-Met) that acts as a constitutively active oncogene. MNNG carcinogen treatment of HOS cells caused this chromosomal rearrangement. Southern blotting, RNA expression analysis, chromosomal mapping, NIH 3T3 transformation assay Cell High 2423252
1989 The c-MET proto-oncogene encodes a heterodimeric receptor tyrosine kinase (p190) comprising a 50 kDa alpha chain disulfide-linked to a 145 kDa beta chain (alpha-beta complex). High tyrosine kinase activity of p190 was identified in gastric tumor cell line GTL-16, accompanied by MET gene amplification and overexpression. Anti-phosphotyrosine immunoprecipitation, non-reducing SDS-PAGE, protein characterization, Southern blotting for gene amplification Nature High 2541345
1993 HGF/SF stimulation of the c-Met receptor activates PI-3 kinase (85 kDa subunit phosphorylated on tyrosine, PI-3K activity associates with c-Met receptor), GAP, PLC-gamma, Src, and MAP kinase as primary signal transduction targets within 10-15 minutes. PI-3 kinase association with c-Met is rapid and direct. In vitro kinase assays, phosphotyrosine immunoprecipitation, biochemical fractionation, signal transduction assays in cell culture EXS Medium 8380734
1996 Ets transcription factors (specifically Ets1) transcriptionally upregulate MET expression by binding to four putative Ets binding sites within the first 300 bp of the MET promoter. Ets1 co-expression enhanced MET promoter activity; Ets decoy oligonucleotides reduced Met protein levels; Met activation in turn induces ETS1 mRNA, forming a positive feedback loop. 5' deletion analysis of MET promoter, transient co-transfection/reporter assays, stable Ets1 transfection, decoy oligonucleotides, Western blotting Oncogene High 8934537
2003 MET signaling drives tubulogenesis via recruitment of the Gab1 adaptor protein and its effector SHP2 tyrosine phosphatase, which are crucial for sustained ERK/MAP kinase pathway activation, epithelial morphogenesis, and dissociation of adherens junctions, in addition to stimulating cellular motility, survival, and proliferation. Review synthesizing branching morphogenesis assays in 3D gels, genetic epistasis using dominant-negative constructs, biochemical signaling studies in epithelial cells Trends in cell biology Medium 12791299
2004 Activated Met receptor undergoes rapid endocytosis and ubiquitin-dependent sorting to the lysosomal degradative pathway. Ubiquitination of Met through the E3 ligase Cbl is required for receptor downregulation. A mutant receptor defective in Cbl binding is able to transform cells, linking impaired trafficking/degradation to oncogenic activation. Endocytic trafficking assays, ubiquitination assays, mutant receptor analysis, cell transformation assays Current topics in microbiology and immunology Medium 15645709
2005 The cytoplasmic C-terminal region of Met acts as a multisubstrate docking site recruiting Grb2, Gab1, STAT3, Shc, SHIP-1, and Src via their PH, PTB, SH2, and SH3 domains. Crystal structure of the Met tyrosine kinase domain provides the molecular framework for understanding substrate specificity. Crystal structure determination, structural analysis of kinase domain, domain interaction studies Molecular and cellular biochemistry Medium 16132696
2008 Three miRNAs (miR-34b, miR-34c, and miR-199a*) negatively regulate MET expression at the translational level. Inhibition of these miRNAs using antagomiRs increased MET protein levels; exogenous expression of these miRNAs in cancer cells blocked MET-induced signal transduction and the invasive growth program, and reduced MET-induced migratory ability of melanoma-derived primary cells. AntagomiR knockdown, miRNA overexpression, Western blotting, signal transduction assays, cell migration assays, MET protein quantification Cancer research High 19074879
2010 Acquired resistance to MET small-molecule inhibitors (PHA-665752, JNJ38877605) in MET-addicted cells occurs through MET gene amplification leading to increased expression and constitutive phosphorylation, followed by amplification and overexpression of wild-type KRAS. KRAS amplification causes progressive loss of MET dependence and acquisition of KRAS dependence. In vitro selection of resistant cells with increasing inhibitor concentrations, gene copy number analysis, Western blotting for phosphorylation, cell viability assays, multiple cell lines and two different inhibitors Cancer research High 20841479
2010 PAX3 and SOX10 directly activate MET expression in melanoma. PAX3 binds elements in the MET promoter independently; SOX10 synergistically activates MET expression with PAX3 or MITF but does not directly activate MET alone. Two pathways exist for PAX3-mediated MET induction: direct activation of the gene, and indirect regulation through MITF. MET promoter binding assays, reporter gene assays, co-transfection experiments, chromatin immunoprecipitation, melanoma cell line analysis Pigment cell & melanoma research Medium 20067553
2011 In MET-addicted cancer cells, Ron kinase is specifically transphosphorylated by activated Met (not by other constitutively active RTKs including EGFR or HER2). Ron phosphorylation is suppressed by Met-specific kinase inhibitors and by antibody-induced shedding of Met from the cell surface. shRNA silencing of RON in MET-addicted cells decreased proliferation, clonogenic activity in vitro, and tumorigenicity in vivo. Co-immunoprecipitation, kinase inhibitor treatment, antibody-induced receptor shedding, shRNA knockdown, in vitro proliferation/clonogenicity assays, in vivo tumorigenicity assay Cancer research High 21212418
2011 Mutant Met receptors bearing kinase-activating mutations (unlike wild-type) circumvent ubiquitin-dependent lysosomal degradation and instead recycle to the plasma membrane via GGA3 adaptor protein recruitment. This recycling is mediated through GGA3 interaction with activated Arf6 and indirect binding to phosphorylated Met through adaptor protein Crk. Mutant receptors elicit enhanced signaling from endosomes critical for cell motility and tumorigenesis. Endocytic trafficking analysis, receptor recycling assays, adaptor protein interaction studies Science signaling Medium 21917713
2011 Crystal structures of Met in complex with L. monocytogenes InlB suggest that Met dimerization is mediated by a dimer contact of the ligand. Structural comparison with HGF/SF reveals parallels and differences in Met activation mechanisms. X-ray crystallography of Met-InlB complex, structural comparison European journal of cell biology Medium 21242015
2014 PAX3 and ETS1 directly interact and synergistically activate MET expression through the 300 bp 5' proximal MET promoter, which contains a PAX3 response element and two ETS1 consensus motifs. ETS1 activates MET via PAX3-dependent and PAX3-independent mechanisms. HGF-dependent ETS1 activation enhances MET expression indirectly, creating a positive feedback loop. Dominant-negative ETS1 reduces melanoma cell growth in culture and in vivo. Promoter reporter assays, co-immunoprecipitation of PAX3-ETS1 interaction, ChIP, siRNA knockdown, dominant-negative constructs, in vivo tumor growth assay Oncogene High 25531327
2015 Somatic splice site alterations at MET exon 14 (METex14) result in exon skipping, loss of the juxtamembrane domain (which contains a negative regulatory region and the Cbl E3 ligase binding site Y1003), and constitutive MET kinase activation leading to oncogenic transformation in vitro. Cells harboring METex14 alterations are sensitive to MET inhibitors. Comprehensive genomic profiling of 38,028 tumor samples, functional in vitro studies of METex14 alterations, MET inhibitor sensitivity assays Cancer discovery High 25971938
2015 MET kinase domain fusions (TRIM4-MET and ZKSCAN1-MET) constitutively activate MAPK, PI3K, and PLCγ1 signaling pathways. These fusion kinases are blocked by MET inhibitors cabozantinib and PF-04217903 at nanomolar concentrations. Identification of MET fusions by genomic analysis, functional characterization of fusion proteins with western blotting for downstream signaling, MET inhibitor treatment assays Nature communications Medium 26013381
2015 A missense mutation c.2521T>G (p.F841V) in MET (encoding the hepatocyte growth factor receptor) is associated with autosomal recessive non-syndromic hearing loss (DFNB97) in humans, mapped to chromosome 7q31.2, establishing MET function in auditory system development. Homozygosity mapping with 1 million SNP array, whole-exome sequencing, Sanger confirmation, cosegregation analysis, absence from 800 control chromosomes Journal of medical genetics Medium 25941349
2015 PTPRZ1-MET (ZM) fusion proteins preserve fundamental properties of wild-type MET with respect to processing and dimerization, and enhance MET phosphorylation in both HGF-dependent and HGF-independent manners. ZM fusions increase MET mRNA expression levels. Western blotting, phosphorylation analysis, dimerization assays, mRNA expression analysis in ZM fusion-carrying patient samples and cell models FEBS letters Medium 25935522
2016 MET signaling in keratinocytes activates EGFR through autocrine EGFR ligand synthesis and release, mediated by the kinase SRC, the pseudoproteases iRhom1 and iRhom2, and the metallopeptidase ADAM17. Pharmacological EGFR inhibition caused regression of MET-driven spontaneous squamous tumors. Transgenic MT-HGF mouse model, keratinocyte culture studies, Western blotting for signaling, pharmacological inhibition of EGFR/SRC/ADAM17, gene expression profiling Science signaling High 27330189
2019 In MET-amplified cancer cells, MET inhibition counteracts IFN-γ-induced PD-L1/PD-L2 upregulation. JAK2 and MET physically associate in the same signaling complex in a MET phosphorylation-dependent manner. MET inhibitors (JNJ-605, MvDN30) neutralize JAK/STAT1 signaling downstream of the IFN-γ receptor, preventing PD-1 ligand induction. Co-immunoprecipitation of MET-JAK2 complex, PD-L1/PD-L2 expression analysis, MET inhibitor treatment, signaling pathway analysis in MET-amplified cell lines and patient-derived tumor organoids British journal of cancer High 30723303
2020 METex14 skipping results in loss of the juxtamembrane domain, retaining HGF affinity but eliminating negative regulatory function, leading to receptor accumulation on the cell surface and prolonged HGF-dependent activation. Review synthesizing functional studies of METex14 deletion consequences on receptor biology Cancer treatment reviews Medium 32334240
2021 ENO1 (alpha-enolase) directly interacts with MET (HGFR) and activates HGFR signaling via increased phosphorylation of HGFR. This interaction activates Wnt coreceptor LRP5/6, decreases GSK3β activity via Src-PI3K-AKT signaling, inactivates the β-catenin destruction complex, and upregulates SLUG and β-catenin to promote EMT and lung cancer metastasis. Co-immunoprecipitation of ENO1-HGFR, Western blotting for phosphorylation, knockdown/overexpression studies, in vivo orthotopic and tail-vein injection models, anti-ENO1 antibody treatment Cancer research High 34145039
2021 MET-deficient neutrophils (MRP8-Cre MET-LoxP mice) show reduced severity of DSS-induced colitis, decreased TH17 cell numbers, and decreased IL-1β production, establishing that neutrophilic HGF-MET signaling promotes intestinal inflammation through IL-1β-mediated TH17 expansion. Conditional knockout mice (MRP8-Cre MET-LoxP), DSS colitis model, flow cytometry for immune cell populations, cytokine quantification Journal of Crohn's & colitis High 32556102
2021 CYP1A2 suppresses HGF/MET signaling by binding to HIF-1α (transcriptional activator of MET) and inducing ubiquitin-mediated degradation of HIF-1α, thereby inhibiting HIF-1α-mediated MET transcription. CYP1A2 also decreases HGF levels, reducing MET activation. Co-immunoprecipitation of CYP1A2-HIF-1α interaction, ubiquitination assays, Western blotting, CYP1A2 overexpression/knockdown studies, in vivo tumor model Theranostics Medium 33500715
2023 Circular MET RNA (circMET) encodes a 404-amino-acid MET variant (MET404) whose translation is facilitated by the m6A reader YTHDF2. MET404 directly interacts with the MET beta subunit forming a constitutively activated MET receptor complex whose activity does not require HGF stimulation. Genetic ablation of circMET in mice attenuates MET signaling; MET404 knock-in plus P53 knockout in mouse astrocytes initiates GBM tumorigenesis. circMET genetic ablation in mice, MET404 knock-in mouse model, co-immunoprecipitation of MET404-MET beta subunit, neutralizing antibody treatment, in vitro and in vivo tumorigenicity assays, YTHDF2 functional studies Nature communications High 37491377
2023 EpCAM extracellular domain (EpEX) physically binds to MET (HGFR) and activates downstream ERK and FAK-AKT signaling, stabilizes active β-catenin and Snail proteins via GSK3β inactivation, and promotes EMT and metastatic potential. EpEX and HGF cooperatively mediate HGFR signaling. Co-immunoprecipitation, ELISA, FRET analysis of EpEX-HGFR interaction, Western blotting for downstream signaling, in vivo metastasis models (tail vein injection and orthotopic) Journal of translational medicine High 37543570

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Targeting MET in cancer: rationale and progress. Nature reviews. Cancer 1219 22270953
2020 EMT, MET, Plasticity, and Tumor Metastasis. Trends in cell biology 799 32800658
2015 Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer discovery 643 25971938
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 563 26729443
1986 Mechanism of met oncogene activation. Cell 536 2423252
1989 Tyrosine kinase receptor indistinguishable from the c-met protein. Nature 482 2541345
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 303 27794501
2012 TFIIH: when transcription met DNA repair. Nature reviews. Molecular cell biology 249 22572993
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 189 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 161 23453860
2008 MicroRNAs impair MET-mediated invasive growth. Cancer research 151 19074879
2017 Targeting MET in cancer therapy. Chronic diseases and translational medicine 149 29063069
2010 MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer research 149 20841479
2007 From Tpr-Met to Met, tumorigenesis and tubes. Oncogene 144 17322912
2011 MET expression and amplification in patients with localized gastric cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 141 21393565
2012 MET signaling regulates glioblastoma stem cells. Cancer research 139 22617325
2015 Activating MET kinase rearrangements in melanoma and Spitz tumours. Nature communications 135 26013381
2015 When plant virology met Agrobacterium: the rise of the deconstructed clones. Plant biotechnology journal 125 26073158
2021 ENO1 Promotes Lung Cancer Metastasis via HGFR and WNT Signaling-Driven Epithelial-to-Mesenchymal Transition. Cancer research 122 34145039
2019 MET in glioma: signaling pathways and targeted therapies. Journal of experimental & clinical cancer research : CR 121 31221203
2015 c-Met as a Target for Personalized Therapy. Translational oncogenomics 120 26628860
1996 Ets up-regulates MET transcription. Oncogene 118 8934537
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 115 27573171
1997 Met-HGF/SF: tumorigenesis, invasion and metastasis. Ciba Foundation symposium 115 9524767
2008 Molecular cancer therapy: can our expectation be MET? European journal of cancer (Oxford, England : 1990) 107 18295476
2020 Reversible EMT and MET mediate amnion remodeling during pregnancy and labor. Science signaling 99 32047115
2008 MET as a target for treatment of chest tumors. Lung cancer (Amsterdam, Netherlands) 98 18672314
2021 HGF and MET: From Brain Development to Neurological Disorders. Frontiers in cell and developmental biology 96 34179015
2020 MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis. OncoTargets and therapy 92 32273721
2015 Artificial human Met agonists based on macrocycle scaffolds. Nature communications 91 25758345
2021 The role of MET in chemotherapy resistance. Oncogene 83 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 82 30069760
2008 HGF and MET mutations in primary and secondary lymphedema. Lymphatic research and biology 82 18564920
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 75 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
2020 The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping. Cancer treatment reviews 66 32334240
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 61 26905592
2009 Targeting the Met signaling pathway in renal cancer. Expert review of anticancer therapy 59 19496715
2023 Circular RNA encoded MET variant promotes glioblastoma tumorigenesis. Nature communications 58 37491377
2009 MET pathway as a therapeutic target. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 58 19333071
1994 The Met/hepatocyte growth factor receptor (HGFR) gene is overexpressed in some cases of human leukemia and lymphoma. Leukemia research 58 8289471
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
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
2020 MET targeting: time for a rematch. Oncogene 51 32034310
2021 Roles of MET in human cancer. Clinica chimica acta; international journal of clinical chemistry 48 34951962
2010 Targeting the MET oncogene in cancer and metastases. Expert opinion on investigational drugs 48 20868306
2015 C-MET overexpression and amplification in gliomas. International journal of clinical and experimental pathology 46 26823824
2015 Gene of the month: MET. Journal of clinical pathology 43 25987653
2010 PAX3 and SOX10 activate MET receptor expression in melanoma. Pigment cell & melanoma research 43 20067553
2020 The METeoric rise of MET in lung cancer. Cancer 40 32888330
2018 Have Clinical Trials Properly Assessed c-Met Inhibitors? Trends in cancer 40 29458966
2014 Physiological Signaling and Structure of the HGF Receptor MET. Biomedicines 40 28536396
2019 Met inhibition revokes IFNγ-induction of PD-1 ligands in MET-amplified tumours. British journal of cancer 39 30723303
2018 The Role of PI3K in Met Driven Cancer: A Recap. Frontiers in molecular biosciences 39 30406111
2014 Targeting MET for glioma therapy. Neurosurgical focus 39 25434379
2004 Met receptor dynamics and signalling. Current topics in microbiology and immunology 39 15645709
2005 MET meet adaptors: functional and structural implications in downstream signalling mediated by the Met receptor. Molecular and cellular biochemistry 38 16132696
2016 Biomarker development in MET-targeted therapy. Oncotarget 37 27013592
2024 Targeting MET in NSCLC: An Ever-Expanding Territory. JTO clinical and research reports 36 38361739
2016 IGF1R and c-met as therapeutic targets for colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 27470393
2013 Targeting MET: why, where and how? Current opinion in pharmacology 36 23797036
2006 MET expression in sporadic renal cell carcinomas. Journal of Korean medical science 36 16891811
2015 A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss. Journal of medical genetics 35 25941349
2014 Targeting Met and Notch in the Lfng-deficient, Met-amplified triple-negative breast cancer. Cancer biology & therapy 35 24556651
2021 CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling. Theranostics 34 33500715
2014 PAX3 and ETS1 synergistically activate MET expression in melanoma cells. Oncogene 34 25531327
2020 Neutrophilic HGF-MET Signalling Exacerbates Intestinal Inflammation. Journal of Crohn's & colitis 33 32556102
2004 Met decoys: will cancer take the bait? Cancer cell 31 15261136
2023 Identification of MET fusions as novel therapeutic targets sensitive to MET inhibitors in lung cancer. Journal of translational medicine 30 36829199
2015 Clinical significance of MET in gastric cancer. World journal of gastrointestinal oncology 30 26600931
2014 Expressions and clinical significances of c-MET, p-MET and E2f-1 in human gastric carcinoma. BMC research notes 30 24393368
2011 Structural insights into Met receptor activation. European journal of cell biology 30 21242015
2009 Inhibition of HGF/MET as therapy for malignancy. Expert opinion on therapeutic targets 29 19397476
2001 Absence of tpr-met and expression of c-met in human gastric mucosa and carcinoma. The Journal of pathology 29 11523050
1993 Signal transduction in c-met mediated motogenesis. EXS 29 8380734
2022 Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors. European journal of cancer (Oxford, England : 1990) 28 36521334
2015 MET deregulation in breast cancer. Annals of translational medicine 28 26366398
2016 Sequence-defined cMET/HGFR-targeted Polymers as Gene Delivery Vehicles for the Theranostic Sodium Iodide Symporter (NIS) Gene. Molecular therapy : the journal of the American Society of Gene Therapy 27 27157666
2016 MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis. Science signaling 27 27330189
2015 Retrospective Review of MET Gene Mutations. Oncoscience 27 26097886
2011 Met receptor: a moving target. Science signaling 27 21917713
2021 When the MET receptor kicks in to resist targeted therapies. Oncogene 26 34031544
2019 The Role of MET in Melanoma and Melanocytic Lesions. The American journal of pathology 26 31476283
2017 Are energy and protein requirements met in hospital? Journal of human nutrition and dietetics : the official journal of the British Dietetic Association 25 28586107
2011 Met interacts with EGFR and Ron in canine osteosarcoma. Veterinary and comparative oncology 25 22235915
2010 The Met receptor tyrosine kinase and basal breast cancer. Cell cycle (Georgetown, Tex.) 25 20237428
2015 MicroRNA and MET in lung cancer. Annals of translational medicine 24 25992367
2012 Targeting the Met pathway in lung cancer. Expert review of anticancer therapy 24 22500688
2020 MET receptor in oncology: From biomarker to therapeutic target. Advances in cancer research 23 32593403
2011 MET and phosphorylated MET as potential biomarkers in lung cancer. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer 23 22181983
2020 When robotics met fluidics. Lab on a chip 22 31895394
2015 Enhanced expression and phosphorylation of the MET oncoprotein by glioma-specific PTPRZ1-MET fusions. FEBS letters 21 25935522
1999 Amplification and overexpression of the hepatocyte growth factor receptor (HGFR/MET) in rat DMBA sarcomas. Oncogene 21 10359528
2023 Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis. Journal of translational medicine 20 37543570

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