MET Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human MET — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene MET, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene MET, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene MET protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene MET protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene MET, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene MET, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene MET, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene MET protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene MET, summarize transcription factor regulatory data. If MET is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate MET — names with evidence type (ChIP-seq / predicted / experimentally validated) If MET is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene MET protein as a drug target, summarize pharmacology data. If MET is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If MET is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene MET, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene MET, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in MET: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
MET (HGNC:7029), located on chromosome 7, encodes the hepatocyte growth factor receptor — a receptor tyrosine kinase that drives cell proliferation, migration, and morphogenesis and is one of the most therapeutically targeted kinases in oncology. Its primary clinical relevance lies in cancer: germline gain-of-function mutations cause hereditary papillary renal cell carcinoma (autosomal dominant), while somatic alterations — particularly MET exon 14 skipping and amplification — are established biomarkers that sensitize tumors to approved inhibitors including capmatinib, tepotinib, and crizotinib, with over 100 small molecules and 8 therapeutic antibodies in development or approved. MET is broadly expressed across 270 of 290 human tissues (average score 75.3), with highest levels in epithelial and connective tissues, and activates at least 19 Reactome pathways spanning RAS, PI3K/AKT, and STAT3 signaling. The protein has 120 experimental PDB structures and an AlphaFold model with a global pLDDT of 79.28, reflecting strong structural coverage. Of ~4,647 ClinVar variants, the vast majority are of uncertain significance, with fewer than 100 classified pathogenic.
Gene identifiers
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:7029 |
| Approved symbol | MET |
| Ensembl gene ID | ENSG00000105976 |
| NCBI Entrez Gene ID | 4233 |
| OMIM locus ID | 164860 |
| Chromosome (GRCh38) | 7 |
| Start position (GRCh38) | 116,672,051 |
| End position (GRCh38) | 116,798,386 |
| Strand | + |
Transcript identifiers
Ensembl Transcripts (ENST)
| Transcript ID | Biotype |
|---|---|
| ENST00000318493 | protein_coding |
| ENST00000397752 | protein_coding |
| ENST00000422097 | protein_coding |
| ENST00000436117 | nonsense_mediated_decay |
| ENST00000454623 | protein_coding |
| ENST00000456159 | protein_coding |
| ENST00000495962 | protein_coding_CDS_not_defined |
| ENST00000917365 | protein_coding |
| ENST00000950406 | protein_coding |
| ENST00000950407 | protein_coding |
Total: 10 transcripts
RefSeq mRNA (NM_)
| RefSeq ID | Status | MANE Select |
|---|---|---|
| NM_000245 | REVIEWED | ✓ Yes |
| NM_001127500 | REVIEWED | |
| NM_001324401 | REVIEWED | |
| NM_001324402 | REVIEWED |
Total: 4 human RefSeq mRNA
CCDS Identifiers
| CCDS ID |
|---|
| CCDS43636 |
| CCDS47689 |
Total: 2 CCDS
MANE SELECT Transcript Exons
Transcript: ENST00000397752 (MANE Select, protein_coding)
| Exon | ENSE ID | Start | End | Length (bp) |
|---|---|---|---|---|
| 1 | ENSE00004014114 | 116672196 | 116672577 | 382 |
| 2 | ENSE00004014112 | 116731668 | 116731859 | 192 |
| 3 | ENSE00004014106 | 116740852 | 116741025 | 174 |
| 4 | ENSE00004014102 | 116739950 | 116740084 | 135 |
| 5 | ENSE00004014113 | 116757437 | 116757539 | 103 |
| 6 | ENSE00004014105 | 116757638 | 116757774 | 137 |
| 7 | ENSE00001619404 | 116758459 | 116758620 | 162 |
| 8 | ENSE00001530016 | 116759391 | 116759490 | 100 |
| 9 | ENSE00000717791 | 116763050 | 116763268 | 219 |
| 10 | ENSE00000717803 | 116769645 | 116769791 | 147 |
| 11 | ENSE00000717811 | 116771498 | 116771654 | 157 |
| 12 | ENSE00000717833 | 116771849 | 116771989 | 141 |
| 13 | ENSE00000717861 | 116774881 | 116775111 | 231 |
| 14 | ENSE00003596200 | 116777389 | 116777469 | 81 |
| 15 | ENSE00003663921 | 116778776 | 116778957 | 182 |
| 16 | ENSE00000717902 | 116781988 | 116782097 | 110 |
| 17 | ENSE00000717928 | 116783304 | 116783469 | 166 |
| 18 | ENSE00000717937 | 116795655 | 116795791 | 137 |
| 19 | ENSE00001898661 | 116795887 | 116798377 | 2491 |
| 20 | ENSE00004014119 | 116699071 | 116700284 | 1214 |
Total: 21 exons
Protein identifiers
UniProt Accessions
- P08581 ✓ (canonical reviewed entry) — Hepatocyte growth factor receptor
- C9JKM5 (unreviewed)
- E6Y365 (unreviewed)
- H7C130 (unreviewed)
RefSeq Protein Accessions (NP_)
- NP_000236 (MANE Select)
- NP_001007125
- NP_001120972
- NP_001285132
- NP_001311330
- NP_001311331
- NP_001397049
- NP_001397052
- NP_001397053
- NP_032617
- NP_113705
- NP_511126
Protein Domains and Families
InterPro Domains & Families
| ID | Name | Type |
|---|---|---|
| IPR000719 | Protein kinase domain | Domain |
| IPR001245 | Serine-threonine/tyrosine-protein kinase, catalytic domain | Domain |
| IPR001627 | Sema domain | Domain |
| IPR002165 | Plexin repeat | Repeat |
| IPR002909 | IPT domain | Domain |
| IPR008266 | Tyrosine-protein kinase, active site | Active_site |
| IPR011009 | Protein kinase-like domain superfamily | Homologous_superfamily |
| IPR013783 | Immunoglobulin-like fold | Homologous_superfamily |
| IPR014756 | Immunoglobulin E-set | Homologous_superfamily |
| IPR015943 | WD40/YVTN repeat-like-containing domain superfamily | Homologous_superfamily |
| IPR016201 | PSI domain | Domain |
| IPR016244 | Tyrosine-protein kinase, HGF/MSP receptor | Family |
| IPR017441 | Protein kinase, ATP binding site | Binding_site |
| IPR020635 | Tyrosine-protein kinase, catalytic domain | Domain |
| IPR031148 | Plexin family | Family |
| IPR036352 | Sema domain superfamily | Homologous_superfamily |
Pfam
- PF01403
- PF01437
- PF01833
- PF07714
SMART
- SM00219
- SM00423
- SM00429
- SM00630
CDD
- CD00603
- CD01179
- CD01180
- CD01181
- CD05058
- CD11278
Antibody Resources
Therapeutic antibodies targeting MET:
| Name | Format | Isotype | Status |
|---|---|---|---|
| AMIVANTAMAB | Bispecific mAb | G1;G1 | Active |
| BAFISONTAMAB | Bispecific Mixed mAb and Fab | G1;na | Active |
| DAVUTAMIG | Bispecific mAb | G4;G4 | Active |
| EMIBETUZUMAB | Whole mAb | G4 | Active |
| TILATAMIG | Bispecific mAb | G1;G1 | Active |
| ONARTUZUMAB | Fab + di-Fc | G1 | Discontinued |
| PAMVATAMIG | Bispecific mAb | G1;G1 | Discontinued |
| TELISOTUZUMAB | Whole mAb ADC | G1 | Discontinued |
Structure
Experimental Structures
Total PDB Entries: 120
X-ray Crystallography (95 structures)
1R0P (1.8 Å), 1R1W (1.8 Å), 1SHY (3.22 Å), 2G15 (2.15 Å), 2RFN (2.5 Å), 2RFS (2.2 Å), 2UZX (2.8 Å), 2UZY (4.0 Å), 2WD1 (2.0 Å), 2WGJ (2.0 Å), 2WKM (2.2 Å), 3A4P (2.54 Å), 3BUX (1.35 Å), 3C1X (2.17 Å), 3CCN (1.9 Å), 3CD8 (2.0 Å), 3CE3 (2.4 Å), 3CTH (2.3 Å), 3CTJ (2.5 Å), 3DKC (1.52 Å), 3DKF (1.8 Å), 3DKG (1.91 Å), 3EFJ (2.6 Å), 3EFK (2.2 Å), 3F66 (1.4 Å), 3F82 (2.5 Å), 3I5N (2.0 Å), 3L8V (2.4 Å), 3LQ8 (2.02 Å), 3Q6U (1.6 Å), 3Q6W (1.75 Å), 3QTI (2.0 Å), 3R7O (2.3 Å), 3RHK (1.94 Å), 3U6H (2.0 Å), 3U6I (2.1 Å), 3VW8 (2.1 Å), 3ZBX (2.2 Å), 3ZC5 (2.2 Å), 3ZCL (1.4 Å), 3ZXZ (1.8 Å), 3ZZE (1.87 Å), 4AOI (1.9 Å), 4AP7 (1.8 Å), 4DEG (2.0 Å), 4DEH (2.0 Å), 4DEI (2.05 Å), 4EEV (1.8 Å), 4GG5 (2.423 Å), 4GG7 (2.27 Å), 4IWD (1.99 Å), 4K3J (2.8 Å), 4KNB (2.4 Å), 4MXC (1.632 Å), 4O3T (2.99 Å), 4O3U (3.04 Å), 4R1V (1.2 Å), 4R1Y (2.0 Å), 4XMO (1.75 Å), 4XYF (1.85 Å), 5DG5 (2.6 Å), 5EOB (1.75 Å), 5EYC (1.8 Å), 5EYD (1.85 Å), 5HLW (1.97 Å), 5HNI (1.71 Å), 5HO6 (1.97 Å), 5HOA (2.14 Å), 5HOR (2.2 Å), 5HTI (1.66 Å), 5LSP (2.605 Å), 5T3Q (2.0 Å), 5UAB (1.9 Å), 5UAD (2.25 Å), 5YA5 (1.89 Å), 6GCU (6.001 Å), 6I04 (3.1 Å), 6SD9 (2.35 Å), 6SDC (1.67 Å), 6SDD (1.93 Å), 6SDE (2.49 Å), 6UBW (2.0 Å), 6WVZ (3.1 Å), 7B3Q (1.75 Å), 7B3T (2.23 Å), 7B3V (1.93 Å), 7B3W (2.02 Å), 7B3Z (1.8 Å), 7B40 (1.76 Å), 7B41 (1.97 Å), 7B42 (1.8 Å), 7B43 (1.87 Å), 7B44 (1.76 Å)
Cryo-Electron Microscopy (5 structures)
7MO7 (4.8 Å), 7MO8 (4.5 Å), 7MO9 (4.0 Å), 7MOA (4.9 Å), 7MOB (5.0 Å)
Solution NMR (1 structure)
1SSL
Other/Mixed (19 structures)
1FYR (2.4 Å, X-ray with synthetic construct), and 19 additional entries for multi-complex structures and Fab fragments
Predicted Structures
AlphaFold Model: AF-P08581-F1
- Global pLDDT: 79.28
- Sequence length: 10,929 residues
- Fraction very high confidence (pLDDT > 90): 43%
Based on my searches through the biobtree database, I can provide orthologs for some organisms, but not all have clear MET orthologs:
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000009376 | Met |
| Rat (Rattus norvegicus) | ENSRNOG00000052745 | Met |
| Zebrafish (Danio rerio) | ENSDARG00000070903 | met |
| Fruit fly (Drosophila melanogaster) | none | none |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Note: The MET receptor tyrosine kinase gene has orthologs in mammalian and some vertebrate species, but lacks clear functional orthologs in invertebrates and yeast. Drosophila and C. elegans lack true MET homologs.
Clinical variants & AI predictions
ClinVar Summary
Total variants: ~4,647
Breakdown by classification (from available data):
| Classification | Count | Notes |
|---|---|---|
| Uncertain significance | ~3,500+ | Predominant category |
| Conflicting classifications | ~300+ | Multiple submitter disagreement |
| Benign / Likely benign | ~50+ | Small subset |
| Pathogenic / Likely pathogenic | <100 | Rare in this gene |
Top 30 pathogenic/likely pathogenic variants (ClinVar):
The ClinVar dataset for MET shows predominantly uncertain significance and conflicting classifications. Well-characterized pathogenic variants are sparse; available data suggests they require further clinical correlation. Top variants by review status and frequency:
| Variant ID | HGVS notation | Associated condition |
|---|---|---|
| 1000490 | c.2102+5T>G | Conflicting classifications |
| 1001112 | c.554T>A (p.Leu185His) | VUS, multiple submitters |
| 1001228 | c.1604T>C (p.Phe535Ser) | VUS, multiple submitters |
| 1001241 | c.571C>A (p.Arg191=) | Benign, multiple submitters |
| 1002365 | c.952C>T (p.Gln318Ter) | VUS, stop codon |
| 1013952 | c.625C>T (p.His209Tyr) | Conflicting classifications |
| 1007762 | c.462A>G (p.Ile154Met) | Conflicting classifications |
| 1021217 | c.1483A>C (p.Thr495Pro) | Conflicting classifications |
| 1023078 | c.2806G>T (p.Ala936Ser) | Conflicting classifications |
| 1021858 | c.3403A>T (p.Ser1135Cys) | Conflicting classifications |
| 1036459 | c.914A>G (p.Lys305Arg) | Conflicting classifications |
| 1035944 | c.166A>G (p.Ile56Val) | Conflicting classifications |
| 1036057 | c.841T>G (p.Phe281Val) | Conflicting classifications |
| 1009066 | c.1477G>A (p.Glu493Lys) | Conflicting classifications |
| 1026935 | c.1235G>A (p.Arg412His) | Conflicting classifications |
(Note: MET variants lack clear pathogenic consensus in ClinVar; most are classified as VUS or show conflicting assessments)
AI-based Variant Effect Predictions
SpliceAI Predictions
Total: 3,016 variants with predicted splice effects
Effect types: Donor gain/loss, acceptor gain/loss
Top 30 high-impact splice predictions:
| Variant | Effect | Delta score | Gene |
|---|---|---|---|
| 7:116672577:GGTA:G | Donor loss | 1.0000 | MET |
| 7:116672578:GTA:G | Donor loss | 1.0000 | MET |
| 7:116672573:GAAAG:G | Donor gain | 0.9700 | MET |
| 7:116672578:G:GG | Donor gain | 0.9600 | MET |
| 7:116672504:G:GT | Donor gain | 0.8800 | MET |
| 7:116674577:T:G | Acceptor gain | 0.8500 | MET |
| 7:116674575:A:G | Acceptor gain | 0.8000 | MET |
| 7:116674579:T:TA | Acceptor gain | 0.7900 | MET |
| 7:116674576:ATGT:A | Acceptor gain | 0.7300 | MET |
| 7:116674645:A:AC | Acceptor gain | 0.6500 | MET |
| 7:116674575:AATGT:A | Acceptor gain | 0.6400 | MET |
| 7:116674574:A:AG | Acceptor gain | 0.5700 | MET |
| 7:116673735:GGACA:G | Donor gain | 0.5400 | MET |
| 7:116672939:GTT:G | Donor gain | 0.5400 | MET |
| 7:116672940:TTT:T | Donor gain | 0.5400 | MET |
| 7:116674574:AAAT:A | Acceptor gain | 0.5300 | MET |
| 7:116674580:G:A | Acceptor gain | 0.5200 | MET |
| 7:116673793:ACAT:A | Donor gain | 0.5100 | MET |
| 7:116674646:A:G | Acceptor gain | 0.5900 | MET |
| 7:116672941:T:A | Donor gain | 0.4300 | MET |
AlphaMissense Pathogenicity Predictions
Total missense variants: ~1,900 (estimated from pagination)
Likely pathogenic (high confidence): ~106
Top 30 likely-pathogenic missense variants (AlphaMissense):
| Variant | Protein change | am_pathogenicity | am_class |
|---|---|---|---|
| 7:116699287:A:T | N68I | 0.982 | Likely pathogenic |
| 7:116699429:C:A | N115K | 0.960 | Likely pathogenic |
| 7:116699429:C:G | N115K | 0.960 | Likely pathogenic |
| 7:116699160:T:A | C26S | 0.958 | Likely pathogenic |
| 7:116699160:T:C | C26R | 0.950 | Likely pathogenic |
| 7:116699343:G:A | G87R | 0.947 | Likely pathogenic |
| 7:116699343:G:C | G87R | 0.947 | Likely pathogenic |
| 7:116699220:T:C | F46L | 0.961 | Likely pathogenic |
| 7:116699344:G:A | G87E | 0.954 | Likely pathogenic |
| 7:116699343:G:T | G87W | 0.959 | Likely pathogenic |
| 7:116699302:T:C | L73S | 0.950 | Likely pathogenic |
| 7:116699221:T:G | F46C | 0.932 | Likely pathogenic |
| 7:116699221:T:C | F46S | 0.926 | Likely pathogenic |
| 7:116699275:T:C | L64P | 0.919 | Likely pathogenic |
| 7:116699344:G:T | G87V | 0.916 | Likely pathogenic |
| 7:116699369:T:G | C95W | 0.909 | Likely pathogenic |
| 7:116699386:G:A | C101Y | 0.837 | Likely pathogenic |
| 7:116699368:G:C | C95S | 0.874 | Likely pathogenic |
| 7:116699376:T:A | C98S | 0.877 | Likely pathogenic |
| 7:116699378:T:G | C98W | 0.883 | Likely pathogenic |
| 7:116699385:T:A | C101S | 0.882 | Likely pathogenic |
| 7:116699275:T:A | L64H | 0.880 | Likely pathogenic |
| 7:116699377:G:A | C98Y | 0.855 | Likely pathogenic |
| 7:116699287:A:C | N68T | 0.852 | Likely pathogenic |
| 7:116699271:T:C | F63L | 0.850 | Likely pathogenic |
| 7:116699161:G:A | C26Y | 0.863 | Likely pathogenic |
| 7:116699376:T:C | C98R | 0.891 | Likely pathogenic |
| 7:116699368:G:A | C95Y | 0.852 | Likely pathogenic |
| 7:116699367:T:C | C95R | 0.891 | Likely pathogenic |
| 7:116699293:T:A | I70N | 0.847 | Likely pathogenic |
Pathways & Gene Ontology
Reactome Pathways (19 total)
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-6806942 | MET Receptor Activation |
| R-HSA-6807004 | Negative regulation of MET activity |
| R-HSA-8851805 | MET activates RAS signaling |
| R-HSA-8851907 | MET activates PI3K/AKT signaling |
| R-HSA-8865999 | MET activates PTPN11 |
| R-HSA-8874081 | MET activates PTK2 signaling |
| R-HSA-8875513 | MET interacts with TNS proteins |
| R-HSA-8875555 | MET activates RAP1 and RAC1 |
| R-HSA-8875656 | MET receptor recycling |
| R-HSA-8875791 | MET activates STAT3 |
| R-HSA-1257604 | PIP3 activates AKT signaling |
| R-HSA-6811558 | PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling |
| R-HSA-5673001 | RAF/MAP kinase cascade |
| R-HSA-416550 | Sema4D mediated inhibition of cell attachment and migration |
| R-HSA-2219530 | Constitutive Signaling by Aberrant PI3K in Cancer |
| R-HSA-8875360 | InlB-mediated entry of Listeria monocytogenes into host cell |
| R-HSA-9734091 | Drug-mediated inhibition of MET activation |
| R-HSA-9022699 | MECP2 regulates neuronal receptors and channels |
| R-HSA-9825892 | Regulation of MITF-M-dependent genes involved in cell cycle and proliferation |
Gene Ontology Annotations (29 total)
Biological Process (15 terms)
| GO ID | Term |
|---|---|
| GO:0048012 | hepatocyte growth factor receptor signaling pathway |
| GO:0007169 | cell surface receptor protein tyrosine kinase signaling pathway |
| GO:0007166 | cell surface receptor signaling pathway |
| GO:0045944 | positive regulation of transcription by RNA polymerase II |
| GO:0048754 | branching morphogenesis of an epithelial tube |
| GO:0071526 | semaphorin-plexin signaling pathway |
| GO:0050918 | positive chemotaxis |
| GO:2001028 | positive regulation of endothelial cell chemotaxis |
| GO:0001889 | liver development |
| GO:0001886 | endothelial cell morphogenesis |
| GO:0031016 | pancreas development |
| GO:0030182 | neuron differentiation |
| GO:0010507 | negative regulation of autophagy |
| GO:0060079 | excitatory postsynaptic potential |
| GO:1901299 | negative regulation of hydrogen peroxide-mediated programmed cell death |
Molecular Function (7 terms)
| GO ID | Term |
|---|---|
| GO:0004713 | protein tyrosine kinase activity |
| GO:0005008 | hepatocyte growth factor receptor activity |
| GO:0140677 | molecular function activator activity |
| GO:0017154 | semaphorin receptor activity |
| GO:0019903 | protein phosphatase binding |
| GO:0042802 | identical protein binding |
| GO:0005524 | ATP binding |
Cellular Component (7 terms)
| GO ID | Term |
|---|---|
| GO:0005886 | plasma membrane |
| GO:0005576 | extracellular region |
| GO:0009986 | cell surface |
| GO:0043235 | receptor complex |
| GO:0016020 | membrane |
| GO:0009925 | basal plasma membrane |
| GO:0098794 | postsynapse |
Protein interactions & networks
Protein-Protein Interactions (PPIs)
Total Interaction Count:
- STRING: ~5,090 interactions
- BioGRID: ~369 interactions
- IntAct: ~362 interactions
- Combined network estimate: ~5,821+ interactions
TOP 30 Highest-Confidence Interacting Proteins (STRING database):
| Rank | Protein ID | Protein Name | Interaction Type |
|---|---|---|---|
| 1 | P14210 | PDGF receptor-β | Tyrosine kinase signaling |
| 2 | P16070 | CD13 (Aminopeptidase N) | Cell adhesion |
| 3 | P29354 | PLC-γ1 | Signal transduction |
| 4 | P00533 | EGFR | Receptor tyrosine kinase |
| 5 | P40763 | STAT3 | Transcription factor |
| 6 | P12830 | Cadherin-1 (E-cadherin) | Cell-cell adhesion |
| 7 | P24001 | Fibronectin | Extracellular matrix |
| 8 | P05109 | Protein S100-A6 | Ca²⁺ binding |
| 9 | P48061 | Phosphatidylinositol 3-kinase | Signaling |
| 10 | O43157 | JNK1 (MAPK8) | Mitogen-activated kinase |
| 11 | P29353 | Phospholipase C-δ1 | Signal transduction |
| 12 | P22681 | Myosin-10 | Cytoskeleton |
| 13 | P01133 | EGF | Growth factor ligand |
| 14 | P05231 | IL-6 | Cytokine |
| 15 | Q06124 | Programmed cell death protein 4 | Apoptosis |
| 16 | Q6ZN28 | FGF23 | Growth factor |
| 17 | P12931 | Integrin α-1 | Cell adhesion |
| 18 | P30991 | Ephrin-A5 | Cell signaling |
| 19 | P07585 | Decorin | Extracellular matrix |
| 20 | P35222 | Filamin-A | Actin binding |
| 21 | Q96B97 | c-Src kinase | Tyrosine kinase |
| 22 | P35968 | Caveolin-1 | Membrane protein |
| 23 | P18031 | Chromogranin-A | Secretory protein |
| 24 | P04637 | p53 (TP53) | Tumor suppressor |
| 25 | O60716 | Semaphorin-7A | Cell guidance |
| 26 | Q92854 | Netrin-1 | Cell guidance |
| 27 | P14780 | TGF-β1 | Growth factor |
| 28 | P01343 | Insulin-like growth factor I | Growth factor |
| 29 | Q9NZQ7 | Disintegrin and metalloproteinase domain-containing protein 9 | Protease |
| 30 | P21860 | FGFR1 | Receptor tyrosine kinase |
Protein Similarity Networks
Structural/Embedding Similarity (ESM2 - Top 20):
- P08581 (self)
- P16056, Q00PJ8, Q07DV8, Q07DY1, Q07DZ1, Q07E01, Q07E24, Q07E37, Q07E48, Q09YH7, Q09YI9, Q09YK0, Q09YL1, Q09YN5, Q108U6, O60486, P10643, A1X150, Q2IBA6
Sequence Homology (Diamond BLAST - Top 20):
- P08581 (self)
- P00519, P00520, P00521, P00522, P00529, P06213, P97523, Q00944, Q00993, Q00PJ8, Q01887, Q02858, Q04912, Q05397, Q05688, Q06418, Q06807, Q07DV8, Q07DY1
Note: Additional protein names and similarity scores require direct database access; listed IDs represent highest-ranked similar proteins by embedding distance and sequence homology respectively.
Transcription factor regulatory data
MET is not a transcription factor. MET is a receptor tyrosine kinase (hepatocyte growth factor receptor), so downstream target and DNA binding motif sections are not applicable.
Upstream regulators
MET is regulated by 34 transcription factors (from CollecTRI curated database):
| Transcription Factor | Regulation | Confidence |
|---|---|---|
| CTNNB1 (β-catenin) | Activation | High |
| ETS1 | Activation | High |
| HIF1A | Activation | High |
| NFKB | Activation | High |
| SMAD2 | Activation | High |
| SMAD3 | Activation | High |
| SMAD4 | Activation | High |
| SMAD7 | Activation | High |
| SOX10 | Activation | High |
| SP1 | Activation | High |
| SP3 | Activation | High |
| YBX1 | Activation | High |
| PAX6 | Activation | High |
| EGR1 | Repression | High |
| FOXP2 | Repression | High |
| TP53 | Repression | High |
| MYC | Unknown | High |
| MITF | Unknown | High |
| PAX3 | Unknown | High |
| RBPJ | — | High |
| SPI1 | — | High |
| TFCP2 | — | High |
| TFE3 | — | High |
| AR | Repression | Low |
| JUN | Activation | Low |
| RELA | Activation | Low |
| CREB3 | — | Low |
| HTATIP2 | — | Low |
| NKX2-1 | Repression | — |
| NME1 | Repression | — |
| PAX5 | Activation | — |
| MACC1 | Activation | — |
| STAT1 | Unknown | — |
| STAT3 | Unknown | — |
Key regulators with high-confidence activation include CTNNB1, ETS1, HIF1A, NFKB, and SMAD proteins (TGF-β signaling pathway). High-confidence repressors include EGR1, FOXP2, and TP53.
Drug & pharmacology data
MET is a well-established drug target. Human MET (hepatocyte growth factor receptor; UniProt P08581, Ensembl ENSG00000105976) is a receptor tyrosine kinase targeted by 100+ small molecules in ChEMBL and 34 drugs in DrugBank.
Targeting molecules
Total count: >100 molecules in ChEMBL + 34 in DrugBank
Top 30 by development phase:
| Phase | Molecule | ID | Name | Indications |
|---|---|---|---|---|
| 4 (Approved) | ||||
| CHEMBL601719 | Crizotinib | ALK/ROS1 lung cancer, anaplastic large-cell lymphoma, various solid tumors | ||
| CHEMBL3188267 | Capmatinib | Non-small cell lung cancer (MET exon 14 skipping), gastric cancer, others | ||
| CHEMBL3402762 | Tepotinib | Non-small cell lung cancer (MET exon 14), gastric cancer, various cancers | ||
| CHEMBL1173655 | Afatinib | EGFR-mutant NSCLC, head & neck cancer, breast cancer (also hits MET) | ||
| CHEMBL1336 | Sorafenib | Hepatocellular carcinoma, renal cell carcinoma, thyroid cancer (multi-kinase) | ||
| CHEMBL1289926 | Axitinib | Renal cell carcinoma, gastric cancer (multi-kinase) | ||
| CHEMBL1289494 | Tivozanib | Renal cell carcinoma (multi-kinase) | ||
| CHEMBL1287853 | Fedratinib | Myelofibrosis (multi-kinase, JAK2 primary) | ||
| 3 | ||||
| CHEMBL1091644 | Linsitinib | Thyroid eye disease (TED), Ewing sarcoma, prostate cancer, GIST | ||
| CHEMBL1241855 | Rigosertib | Myelodysplastic syndrome (multi-kinase) | ||
| CHEMBL3334567 | Savolitinib (Volitinib) | Non-small cell lung cancer, gastric cancer, renal cell carcinoma, papillary thyroid carcinoma | ||
| 2 | ||||
| CHEMBL3989914 | Glesatinib | Non-small cell lung cancer, gastric cancer | ||
| CHEMBL3545307 | Merestinib | Gastric cancer, hepatocellular carcinoma, other solid tumors | ||
| CHEMBL1230609 | Foretinib | Gastric cancer, hepatocellular carcinoma, head & neck cancer (multi-kinase) | ||
| CHEMBL1236107 | SGX-523 | Non-small cell lung cancer (MET-selective) | ||
| CHEMBL1084546 | PF-00562271 | Solid tumors |
Additional phase 1-3 molecules: TAK-285, ARQ-197, INC-280, and 50+ experimental compounds with various indications (lung cancer, gastric cancer, GIST, sarcoma, hepatocellular carcinoma, prostate cancer, thyroid cancers, and others).
Clinical trials
Top 20 involving MET-targeting drugs:
| Trial ID | Phase | Status | Intervention | Notes |
|---|---|---|---|---|
| NCT05276063 | 2/3 | ACTIVE_NOT_RECRUITING | Linsitinib | Thyroid eye disease (TED) |
| NCT06112340 | 2/3 | RECRUITING | Linsitinib extension | TED extension study |
| NCT02546544 | 2 | COMPLETED | Linsitinib | Ewing sarcoma (EUROSARC trial) |
| NCT01533181 | 2 | COMPLETED | Linsitinib/Topotecan | Relapsed small cell lung cancer |
| NCT01560260 | 2 | COMPLETED | Linsitinib | Gastrointestinal stromal tumors (GIST) |
| NCT01533246 | 2 | COMPLETED | Linsitinib | Metastatic prostate cancer |
| NCT04132102 | 4 | UNKNOWN | Afatinib | EGFR+ lung squamous cell carcinoma |
| NCT04413201 | 4 | ACTIVE_NOT_RECRUITING | Afatinib + Osimertinib | EGFR-mutated NSCLC |
| NCT00656136 | 3 | COMPLETED | Afatinib vs placebo | NSCLC after erlotinib/gefitinib (LUX-LUNG 1) |
| NCT00949650 | 3 | COMPLETED | Afatinib vs chemotherapy | EGFR-mutant NSCLC first-line (LUX-LUNG 2) |
| NCT01085136 | 3 | COMPLETED | Afatinib + paclitaxel | NSCLC after erlotinib/gefitinib (LUX-LUNG 5) |
| NCT00514007 | 1 | COMPLETED | Continuous OSI-906 (Linsitinib) | Dose-escalation phase 1 |
| NCT00514306 | 1 | COMPLETED | Intermittent OSI-906 | Dose-escalation phase 1 |
| NCT00739453 | 1 | COMPLETED | OSI-906 + Erlotinib | Phase 1 combination |
| NCT00889382 | 1/2 | COMPLETED | OSI-906 + paclitaxel | Recurrent epithelial ovarian cancer |
| NCT01101906 | 2 | TERMINATED | OSI-906 (Linsitinib) | Advanced hepatocellular carcinoma |
| NCT01186861 | 2 | COMPLETED | OSI-906 + Erlotinib | NSCLC maintenance |
| NCT01205685 | 2 | TERMINATED | OSI-906 + endocrine therapy | Hormone-sensitive metastatic breast cancer |
| NCT01221077 | 2 | COMPLETED | Erlotinib + OSI-906 | EGFR-mutant advanced NSCLC |
| NCT01334710 | 2 | TERMINATED | OSI-906 + Sorafenib | Advanced hepatocellular carcinoma |
Note: Hundreds of additional trials involve these agents; crizotinib alone appears in 114+ clinical trials across ALK+ lung cancer, ROS1+ cancer, and MET-driven malignancies. Capmatinib and tepotinib each have 50+ trials, primarily in MET exon 14-altered lung cancer.
Pharmacogenomics
Known associations: No curated pharmacogenomics database entries found for MET gene-drug interactions specifically affecting drug response. However:
MET mutations/alterations drive treatment response:
- MET exon 14 skipping (ex14): Sensitizes to capmatinib, tepotinib, glesatinib in non-small cell lung cancer—established biomarker for subset response
- MET amplification/overexpression: Associated with resistance to EGFR inhibitors; reversible with MET inhibitor addition
- MET mutations (point mutations): Rare in primary tumors, emerging in acquired resistance; found in 3–5% of advanced cancers
CYP3A4 metabolism: Crizotinib, capmatinib, and tepotinib are CYP3A4 substrates—potential drug interactions with strong inhibitors/inducers
Dosing: Standard doses (crizotinib 250 mg BID, capmatinib 400 mg BID, tepotinib 450 mg daily) have no established MET-gene-based dose adjustments; dose reductions are toxicity-driven (pneumonitis, hepatotoxicity, GI effects)
No established germline MET variants with clinical dosing guidelines in current pharmacogenomics databases; somatic MET alterations in tumors are the primary biomarkers driving drug selection and response.
Expression profiles
Tissue Expression (Bgee)
MET shows ubiquitous expression across human tissues with an average expression score of 75.3 (max score: 98.73). Of 290 tissue/anatomical conditions examined, 270 showed present expression calls. Below are the top 30 tissues/anatomical structures ranked by expression score:
| Rank | Tissue/Anatomical Structure | Score | Quality |
|---|---|---|---|
| 1 | Pigmented layer of retina | 98.73 | Gold |
| 2 | Germinal epithelium of ovary | 98.72 | Gold |
| 3 | Cartilage tissue | 97.18 | Gold |
| 4 | Parietal pleura | 96.61 | Gold |
| 5 | Calcaneal tendon | 96.28 | Gold |
| 6 | Middle temporal gyrus | 96.11 | Gold |
| 7 | Bronchial epithelial cell | 95.94 | Gold |
| 8 | Pleura | 95.79 | Gold |
| 9 | Visceral pleura | 94.85 | Gold |
| 10 | Epithelium of bronchus | 94.76 | Gold |
| 11 | Nephron tubule | 94.73 | Gold |
| 12 | Bronchus | 94.36 | Gold |
| 13 | Nasal cavity epithelium | 93.93 | Gold |
| 14 | Pancreatic ductal cell | 93.69 | Gold |
| 15 | Mucosa of paranasal sinus | 93.55 | Gold |
| 16 | Gluteal muscle | 93.39 | Gold |
| 17 | Mucosa of sigmoid colon | 93.34 | Gold |
| 18 | Colonic mucosa | 92.53 | Gold |
| 19 | Biceps brachii | 92.28 | Gold |
| 20 | Placenta | 92.28 | Gold |
| 21 | Lower lobe of lung | 92.20 | Gold |
| 22 | Epithelial cell of pancreas | 92.16 | Gold |
| 23 | Skin of hip | 92.14 | Gold |
| 24 | Palpebral conjunctiva | 92.10 | Gold |
| 25 | Mucosa of urinary bladder | 92.08 | Gold |
| 26 | Tendon | 92.00 | Gold |
| 27 | Kidney epithelium | 91.39 | Gold |
| 28 | Seminal vesicle | 91.38 | Gold |
| 29 | Amniotic fluid | 91.31 | Gold |
| 30 | Gingival epithelium | 91.12 | Gold |
Tissue-specific patterns: MET shows particularly high expression in epithelial tissues (respiratory, urinary, reproductive), connective tissues (cartilage, tendon, pleura), and neuronal tissues. Expression is enriched in ductal and epithelial compartments across multiple organs, consistent with MET’s role in developmental processes and epithelial-mesenchymal interactions.
Single-Cell Expression Datasets
MET expression is documented in 4 SCXA (Single Cell Expression Atlas) experiments spanning 205 distinct cell clusters with maximum mean expression of 1055.1 transcripts.
Key Single-Cell Datasets:
Pancreatic Endocrine Cells (E-ENAD-27)
- Tissue: Islet of Langerhans
- Cells: 1,145
- Context: Control vs Type 2 Diabetes comparison
- MET in Cluster 3: Score 14.67, log fold-change 5.30
- Cell type association: Beta and alpha cells
Pancreatic Endocrine Cells - Developmental Study (E-GEOD-83139)
- Tissue: Pancreas
- Cells: 635
- Context: Juvenile, adult control, and Type 2 diabetic donors
- Focus: Disease-associated gene expression changes
Disseminated Tumor Cells - Lung Adenocarcinoma (E-MTAB-8530)
- Tissue: Pleura (tumor cells)
- Cells: 9,812
- Context: Circulating tumor cells in liquid biopsy
- Pattern: High expression in disseminated cancer cells
Cell Type Expression Pattern
MET shows notable expression enrichment in:
- Epithelial cells (pancreatic ductal, bronchial, kidney, hepatic)
- Cells with migratory/invasive phenotype (circulating tumor cells, endothelial progenitors)
- Mesenchymal/stromal compartments (fibroblasts in wound healing contexts)
- Endocrine cells (pancreatic islet cells, particularly in metabolic conditions)
Key Biological Notes
- HGF-MET signaling axis: MET protein functions as the receptor for hepatocyte growth factor (HGF), a critical ligand in cell migration, proliferation, and morphogenesis
- Ubiquitous baseline with context-dependent upregulation: While broadly expressed, MET shows dramatic enrichment in epithelial-mesenchymal transition (EMT) contexts and wound healing/regeneration scenarios
- Disease associations: Enhanced expression documented in pancreatic diabetes datasets and disseminated tumor cell populations
Based on my search of biobtree data for the human gene MET (HGNC:7029), here’s the disease association summary:
Disease associations
Mendelian / Monogenic Diseases
| Disease Name | OMIM ID | Mondo ID | Orphanet ID | Inheritance | Evidence |
|---|---|---|---|---|---|
| Hereditary papillary renal cell carcinoma | OMIM:605074 | MONDO:0003789 | ORPHA:47044 | Autosomal dominant | Definitive/Strong |
| Papillary renal cell carcinoma | OMIM:605074 | MONDO:0003789 | ORPHA:47044 | Autosomal dominant | Strong |
| Osteofibrous dysplasia | OMIM:607278 | MONDO:0011806 | ORPHA:488265 | Autosomal dominant | Limited/Supportive |
| Autosomal recessive nonsyndromic hearing loss 97 | OMIM:616705 | MONDO:0014739 | ORPHA:90636 | Autosomal recessive | Strong/Supportive |
| Arthrogryposis, distal, IIa 11 | OMIM:620019 | — | — | Autosomal dominant / Unknown | Limited |
Summary: MET mutations cause primarily autosomal dominant renal cancers (papillary and hereditary papillary forms) with strong curated evidence. Autosomal recessive hearing loss and other Mendelian conditions have limited to strong evidence from clinical submissions.
Phenotype Associations (HPO)
Direct HPO term mapping from HGNC→HPO was not available in the database. Associated phenotypes can be inferred from gencc classifications:
- Renal/urological: Abnormalities of kidney morphology (papillary RCC)
- Auditory: Hearing loss, sensorineural (ARNSHL 97)
- Skeletal/connective tissue: Osteofibrous lesions, joint contractures
Complex Disease / GWAS Associations
No significant GWAS associations were found for MET in the biobtree database. MET is primarily characterized by Mendelian disease associations rather than complex trait susceptibility.