MET met proto-oncogene (hepatocyte growth factor receptor)

2001-10-01   Debora Angeloni , Michael L. Nickerson , Laura Schmidt 

Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research Facility Bldg. 560 Rm. 12 26 Frederick, MD 21702, USA

Identity

HGNC
LOCATION
7q31.2
LOCUSID
ALIAS
AUTS9,DFNB97,HGFR,RCCP2,c-Met
FUSION GENES

DNA/RNA

Atlas Image
The coding sequence (4173 bp) is represented as red boxes (exons coding for the extracellular domain), blue boxes (sequence coding for the intracellular part) and a green box (coding for the transmembrane domain). Black triangles indicate the splicing sites. Several structural/functional elements are indicated, described in the text.

Description

The human MET gene spans more than 120 kb in length and consists of 21 exons separated by 20 introns . The size of the exons range from 81 bp (exon 16) to about 4kb (exon 21) The size of introns ranges from 0.1 to about 26 kb. The first exon encodes the 5 untranslated region (UTR) (394 bp) of the MET transcript and is separated by 26 kb circa from the second exon. Exon 2 is the largest coding exon, it contains14 bp of 5 UTR and encodes for 400 amino acids. The cleavage site that yields the a- and b-subunits from the precursor polypeptide is encoded by exon 2. Exon 13 contains the hydrophobic transmembrane domain, together with the end of the extracellular domain and the beginning of the intracellular domain. Exons 14 to 21 code for the intracellular part and exons 15 to 21 for the kinase domain. Exon 21 includes the region coding for the carboxy terminus of the protein and the large 3 UTR of the gene. The ATP binding site is encoded for by exon 16; the autophosphorylation site by exon 19; the SH2 docking site by exon 21.

Transcription

Alternative splicing: Multiple MET transcripts of different size were identified in human cell lines and tissues. At least three 8-kb variants were described and presumed to be generated by alternative splicing. A MET isoform was described that lacks 18 amino acids in the extracellular region (exon 10) and is the most abundant form in a variety of tissues and cell lines . Alternative splicing of exon 14 generates another variant that has an in-frame deletion of 47 amino acids in the juxtamembrane cytoplasmic domain of the receptor. A possible mechanism of alternative splicing could be at the origin of a 85 kDa, N-terminally truncated form of MET found in malignant musculo-skeletal tumors, although this short form could also originate from alternative transcription start or proteolitic cleavage.

Proteins

Atlas Image
Red: SEMA domain. Yellow: PSI domain. Green: IPT domains. Black: transmembrane domain. Blue: tyrosine kinase domain. Light blue: C-terminal region. Pink: cell membrane. Y1252, Y11253: autophosphorylation site. Y1367, Y1374: docking site.

Description

The MET receptor (1408 amino acids) is initially synthesized as a partially glycosylated 170 kDa single chain precursor. Following further glycosylation, it is cleaved at a basic amino acid site into an a- and b-chain. The mature form is a transmembrane heterodimer composed of a- and b-chain linked together by disulphide bridges. The 50 kDa a-chain (amino acids 1-307) is located entirely extracellularly and contains the ligand binding pocket. The 140 kDa b-chain (amino acids 308-1408) comprises an extracellular part, the membrane spanning region and an intracellular C-terminal region that contains the tyrosine kinase domain. The C-terminal tail contains a conserved two-tyrosine multifunctional docking site that interacts with multiple SH2-containing intracellular signal transducers. The 5 alternative splicing leads to a form with 1390 amino acids.

Expression

MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) are expressed in numerous tissues although predominantly in cells of epithelial and mesenchymal origin, respectively. MET is amplified and overexpressed in many types of tumors, including tumors of the kidney (see below), thyroid, pancreas and osteosarcoma.

Localisation

MET is a transmembrane tyrosine kinase receptor. Upon ligand binding, the receptor is rapidly internalized, polyubiquitinated and degraded in a proteasome-dependent manner.

Function

The tyrosine kinase MET is the high affinity receptor for HGF/SF, a multifunctional cytokine. Upon ligand binding, MET dimerizes and transphosphorylates tyrosine residues in the C-terminal domain, which then interacts with members of a variety of signaling pathways. These include Grb-2 associated binder 1, phosphoinositide 3 kinase and c-Src. Under physiological conditions, MET-HGF/SF signaling has been shown to affect a wide range of biological activities depending on the cell target. These activities vary from cell proliferation (mitogenesis) to cellular shaping (morphogenesis) and motility (motogenesis). The coordination of these diverse activities constitutes a genetic program of invasive growth that allows branched morphogenesis (the formation of epithelial tubular structures), myoblast migration and neurite branching. MET/HGF cell targets comprise epithelial and mesenchymal cells, hematopoietic cells, myoblasts, spinal motor neurons. MET-HGF/SF signaling is also essential for normal development: mouse embryos carrying null mutations in both HGF alleles die in midgestation and show impaired liver formation.

Homology

MET amino acid sequence shows overall 33% identity with RON (the macrophage stimulating protein (MSP) receptor), which increases to 64% in the kinase domain. MET and RON are grouped in the family of so called scatter factor receptors. However, some structural domains shared by MET and RON are also present in other proteins such as semaphorins and plexins (semaphorins receptors), so that these proteins altogether are thought to originate from a common ancestor. The common domains are: the SEMA domain, a conserved box encompassing about 500 amino acids, with several highly conserved cysteines, and the PSI domain (from Plexin Semaphorins Integrines), of about 50 amino acids with 8 conserved cysteines, found also in integrins. Another structural motif repeated four times in the extracellular region of MET is the IPT domain, an immunoglobulin-like fold shared also by plexins and transcription factors. The function of these domains is at present under investigation but they are thought to mediate protein-protein interactions possibly related to cell dissociations and motility.

Mutations

Germinal

Germline mutations in the MET proto-oncogene are responsible for hereditary papillary renal carcinoma (HPRC) type 1 (see below). 10 known mutations are clustered in exons 16-19 of the tyrosine kinase domain and all are missense mutations which change the amino acid (V1110I, H1112R, H1112Y, M1149T, V1206L, V1238I, D1246N, Y1248C, Y1248D, M1268T). Mutations at four codons (V1110, D1246, Y1248, M1268) are homologous to sites of disease-associated activating mutations in other RTKs ( RET, c-kit, c-erbB. Two unrelated North American families have been identified with the H1112R mutation and shared flanking genotyping data, suggesting a founder effect. Most HPRC-associated MET mutations are constitutively activating, causing phosphorylation on tyrosine in a ligand-independent manner when transfected into NIH3T3 cells, and oncogenic when the mutant MET transfected cell lines are injected into nude mice. Other mutations with only weak transforming potential (Y1248C, L1213V) confer anchorage-independent growth and an invasive phenotype in transfected cells.

Somatic

Somatic missense mutations (H1112Y, H1112L, H1124D, L1213V, D1246H, Y1248H, Y1248C, M1268T) were identified in the TK domain of MET in 13% (17/129) of sporadic papillary renal carcinoma (PRC) type 1; 15 different germline and somatic MET mutations in 10 codons of the TK domain were identified in PRC. Infrequently, MET mutations have been identified in childhood hepatocellular carcinoma (3/10 in TK domain, T1191I, K1262R, M1268I), gastric carcinoma (1/85 in juxtamembrane domain, P1009S), glioma (1/11 in TK domain, G1137V;) and lymph node metastases (4/15 head and neck squamous cell carcinomas, Y1253D, Y1248C).

Implicated in

Entity name
Hereditary papillary renal carcinoma and Sporadic papillary renal carcinoma (HPRC, SPRC)
Disease
An inherited autosomal dominant form of renal carcinoma with reduced penetrance comprising 10% of all carcinomas of the kidney. Affected family members develop, in the fourth or fifth decade of life, bilateral, multifocal renal tumors with a papillary growth pattern which can be subdivided by histology into type 1 and type 2. Multiple tumors were shown to arise from independent clones. Sporadic PRCs are usually solitary tumors with microscopic papillary lesions in the surrounding renal parenchyma. It is important to note that patients with germline mutations in the MET gene are predisposed to develop papillary renal carcinoma type 1 specifically. These mutations are not known to predispose to any other type of malignant disease.
Prognosis
HPRC is a rare disease with an estimate incidence of 1 in 1 million. The age of development of PRCs is best studied in patients with H1112R mutation, because an elevated number of them has been described. By age 55, one half of H1112R mutation carriers have developed a detectable disease. Also, in H1112R mutation carriers has been observed that 26 % of patients develop distant metastases. The complete expression of the PRC phenotype may be affected by modifier genes. In fact, not only the age of onset varies among individuals but also the severity of the disease: in one patient were found at least 100 renal tumors, whereas his two brothers had a total of 1.
Cytogenetics
Papillary renal tumors are characterized by trisomy of chromosome 7 and 17, loss of Y in males. Only type 1 sporadic and hereditary PRCs harbor MET mutations with nonrandom duplication of the chromosome 7 bearing the mutant MET allele.
Hybrid gene
MET was first identified as the product of a human oncogene, tpr-MET, which derives from the fusion of two distinct genetic loci: tpr (translocated promoter region), which contributes two leucine zipper motifs (a protein-protein dimerization domain), and MET, which contributes the intracellular kinase domain of the MET receptor. The tpr gene sequence involved in the tpr-MET fusion is found on 1q25, though this gene is located at 1q31 in a database
Fusion protein
The tpr-MET chimeric protein is dimerized and activated in ligand-independent manner and therefore possesses constitutive kinase activity and transforming ability.
Atlas Image
The hybrid protein is made of Tpr leucine zippers (red)   that mediate constitutive dimerization - and MET kinase domains (blue), that drive transphosphorylation and constitutive activation.
Oncogenesis
MET/HGF signaling has been implicated in the generation and progression of a variety of tumors. The coexpression of wild type MET and HGF in the same cell (which generates an autocrine stimulatory loop) induces oncogenic transformation.
All investigated naturally occurring MET mutants show increased tyrosine phosphorylation level and enhanced kinase activity. In general, somatic mutations cause higher level of enzymatic activity compared to germline mutants. The kinase domain mutations cause ligand-independent activation and increase the tyrosine kinase activity. The juxtamembrane P1009I mutation does not cause ligand-independent activation but results in prolonged HGF-activated MET response.
The M1268T mutation identified in PRC   homologous to the M918T mutation of RET in multiple endocrine neoplasia type 2b   results not only in increased level of catalytic activity but also in a change of substrate specificity. Whereas c-Src is transiently activated by wild type MET, M1268T mutant MET is stably associated with c-Src, which is thereby constitutively phosphorylated and activated. Also, wild type MET does not phosphorylate substrate for cytosolic kinase c-Abl, whereas M1268T MET does. Moreover, expression of M1268T MET in NIH3T3 causes activation of the b-catenin pathway.
Different mutations act through distinct mechanisms and result in variable transforming activity. D1246H/N and M1268 mutants (that activate the Ras pathway) have high transforming ability. Y1248C and L1213V have less transforming ability but promote cell migration and invasion via activation of the PI3K/AKT pathway
3D molecular modeling studies using the crystal structure of the insulin receptor tyrosine kinase domain as a model suggest that disease-causing MET mutations interfere with the intrasteric mechanism of tyrosine kinase auto-inhibition to destabilize the inactive form and facilitate transition to the active form. Mutations V1110I, Y1248H/D/C, M1268T can affect contact between residues of the activation loop in its inhibitory conformation. Mutations M1149T and L1213V may increase flexibility of the tertiary structure. D1246N can stabilize the kinase in its active conformation. This structural work gives hints to understanding the switch of substrate specificity by mutant receptors.

Bibliography

Pubmed IDLast YearTitleAuthors
106377621999Plexins, semaphorins, and scatter factor receptors: a common root for cell guidance signals?Artigiani S et al
94262011997"Invasive-growth" signaling by the Met/HGF receptor: the hereditary renal carcinoma connection.Bardelli A et al
103906131999Domains in plexins: links to integrins and transcription factors.Bork P et al
18467061991Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product.Bottaro DP et al
114333112001Pathway specificity for Met signalling.Comoglio PM et al
105799141999Plasminogen-related growth factor and semaphorin receptors: a gene superfamily controlling invasive growth.Comoglio PM et al
65909671984Molecular cloning of a new transforming gene from a chemically transformed human cell line.Cooper CS et al
114860252001Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway.Danilkovitch-Miagkova A et al
91955691997Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors.Delahunt B et al
107343142000Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas.Di Renzo MF et al
93804101997Gene structure of the human MET proto-oncogene.Duh FM et al
97152751998Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours.Fischer J et al
76918851993Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product.Furitsu T et al
106579962000Different point mutations in the met oncogene elicit distinct biological properties.Giordano S et al
88920551996Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis.Jeffers M et al
93266291997Activating mutations for the met tyrosine kinase receptor in human cancer.Jeffers M et al
90012341997Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome pathway.Jeffers M et al
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81093221993Molecular cytogenetics of renal cell tumors.Kovacs G et al
75184571994Identification of a novel type of alternative splicing of a tyrosine kinase receptor. Juxtamembrane deletion of the c-met protein kinase C serine phosphorylation regulatory site.Lee CC et al
110426812000A novel germ line juxtamembrane Met mutation in human gastric cancer.Lee JH et al
96661141998The human hepatocyte growth factor receptor gene: complete structural organization and promoter characterization.Liu Y et al
104339441999Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype.Lubensky IA et al
100228661999The Gab1 PH domain is required for localization of Gab1 at sites of cell-cell contact and epithelial morphogenesis downstream from the met receptor tyrosine kinase.Maroun CR et al
113540042001Structural basis of oncogenic activation caused by point mutations in the kinase domain of the MET proto-oncogene: modeling studies.Miller M et al
78519061994Refined localization of the human TPR gene to chromosome 1q25 by in situ hybridization.Miranda C et al
110070372000Missense mutation of the MET gene detected in human glioma.Moon YW et al
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Other Information

Locus ID:

NCBI: 4233
MIM: 164860
HGNC: 7029
Ensembl: ENSG00000105976

Variants:

dbSNP: 4233
ClinVar: 4233
TCGA: ENSG00000105976
COSMIC: MET

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000105976ENST00000318493P08581
ENSG00000105976ENST00000318493A0A024R728
ENSG00000105976ENST00000397752P08581
ENSG00000105976ENST00000397752A0A024R759
ENSG00000105976ENST00000422097H7C174
ENSG00000105976ENST00000436117P08581
ENSG00000105976ENST00000454623H7C130
ENSG00000105976ENST00000456159C9JKM5

Expression (GTEx)

0
5
10
15
20
25

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Axon guidanceKEGGko04360
Focal adhesionKEGGko04510
Adherens junctionKEGGko04520
Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
Renal cell carcinomaKEGGko05211
MelanomaKEGGko05218
Cytokine-cytokine receptor interactionKEGGhsa04060
Axon guidanceKEGGhsa04360
Focal adhesionKEGGhsa04510
Adherens junctionKEGGhsa04520
Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
Pathways in cancerKEGGhsa05200
Renal cell carcinomaKEGGhsa05211
MelanomaKEGGhsa05218
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
MalariaKEGGko05144
MalariaKEGGhsa05144
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Central carbon metabolism in cancerKEGGhsa05230
Central carbon metabolism in cancerKEGGko05230
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Infectious diseaseREACTOMER-HSA-5663205
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
Sema4D in semaphorin signalingREACTOMER-HSA-400685
Sema4D mediated inhibition of cell attachment and migrationREACTOMER-HSA-416550
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
RET signalingREACTOMER-HSA-8853659
Signaling by METREACTOMER-HSA-6806834
MET Receptor ActivationREACTOMER-HSA-6806942
MET activates RAS signalingREACTOMER-HSA-8851805
MET activates PI3K/AKT signalingREACTOMER-HSA-8851907
MET activates PTPN11REACTOMER-HSA-8865999
MET promotes cell motilityREACTOMER-HSA-8875878
MET activates PTK2 signalingREACTOMER-HSA-8874081
MET interacts with TNS proteinsREACTOMER-HSA-8875513
MET activates RAP1 and RAC1REACTOMER-HSA-8875555
MET activates STAT3REACTOMER-HSA-8875791
MET receptor recyclingREACTOMER-HSA-8875656
Negative regulation of MET activityREACTOMER-HSA-6807004
Listeria monocytogenes entry into host cellsREACTOMER-HSA-8876384
InlB-mediated entry of Listeria monocytogenes into host cellREACTOMER-HSA-8875360

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA165946122crizotinibChemicalMultilinkAnnotationassociated22162641

References

Pubmed IDYearTitleCitations
174632502007MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.1601
226350052012Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.1089
234709652013Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.633
180939432007MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.571
201292492010Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.382
127268612003Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.380
221377952011Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.261
181804592008Signaling networks assembled by oncogenic EGFR and c-Met.212
227895362012VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex.209
190066482009miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells.171

Citation

Debora Angeloni ; Michael L. Nickerson ; Laura Schmidt

MET met proto-oncogene (hepatocyte growth factor receptor)

Atlas Genet Cytogenet Oncol Haematol. 2001-10-01

Online version: http://atlasgeneticsoncology.org/gene/131/met