* 164860

MET PROTOONCOGENE, RECEPTOR TYROSINE KINASE; MET


Alternative titles; symbols

MET PROTOONCOGENE
ONCOGENE MET
HEPATOCYTE GROWTH FACTOR RECEPTOR; HGFR


HGNC Approved Gene Symbol: MET

Cytogenetic location: 7q31.2     Genomic coordinates (GRCh38): 7:116,672,196-116,798,377 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q31.2 ?Arthrogryposis, distal, type 11 620019 AD 3
?Deafness, autosomal recessive 97 616705 AR 3
{Osteofibrous dysplasia, susceptibility to} 607278 AD 3
Hepatocellular carcinoma, childhood type, somatic 114550 3
Renal cell carcinoma, papillary, 1, familial and somatic 605074 3

TEXT

Cloning and Expression

Cooper et al. (1984) cloned a transforming gene from a chemically transformed human osteosarcoma-derived cell line and mapped it to 7p11.4-qter. Identity to all previously known oncogenes except ERBB (131550) was ruled out by the fact that they are encoded by other chromosomes; identity to ERBB is probably excluded by failure of direct hybridizations of the 2 probes. MET was the designation suggested by Cooper et al. (1984).

Dean et al. (1985) showed that MET is in the tyrosine kinase family of oncogenes. It appeared to be most closely related in sequence to the human insulin receptor and ABL oncogene.

From the sequence of MET cDNA, Park et al. (1987) concluded that this oncogene is a cell-surface receptor for a then unknown ligand. The c-Met protooncogene product is a receptor-like tyrosine kinase composed of disulfide-linked subunits of 50 kD (alpha) and 145 kD (beta). In the fully processed c-Met product, the alpha subunit is extracellular, and the beta subunit has extracellular, transmembrane, and tyrosine kinase domains as well as sites of tyrosine phosphorylation.

By immunohistochemical staining and Western blot analysis in lesional tissue from affected members of 2 unrelated families with osteofibrous dysplasia (607278; see MOLECULAR GENETICS), Gray et al. (2015) demonstrated the presence of MET in both osteoblasts and osteoclasts. An assay on metaphyseal bone obtained from an age-matched healthy individual also showed detectable levels of MET.


Mapping

By in situ hybridization, Dean et al. (1985) assigned the MET gene to 7q21-q31, where it is tightly linked to CF (219700) which is thought to be located in the proximal part of 7q22. It is about 10 cM from TCRB (see 186930) and is in a region that is associated with nonrandom chromosomal deletions in some patients with acute nonlymphocytic leukemia.

Dean et al. (1987) demonstrated that the Met oncogene is located on chromosome 6 in the mouse, where it is tightly linked to an obesity mutation ('ob').


Gene Function

Bottaro et al. (1991) demonstrated that the beta-subunit of the c-Met protooncogene product is the cell-surface receptor for hepatocyte growth factor (HGF; 142409).

Cooper (1992) reviewed the development of understanding of the MET oncogene in an article subtitled 'From detection by transfection to transmembrane receptor for hepatocyte growth factor.'

Using in situ hybridization and immunoblotting, Powell et al. (2001) detected expression of HGF and MET in the cerebral wall and ganglionic eminence of the developing mouse forebrain. Using scatter assays, Powell et al. (2001) concluded that motogenic activity in the forebrain is due to HGF.

Giordano et al. (2002) presented evidence for cross-talk between the semaphorin 4D (SEMA4D; 601866) receptor, plexin B1 (PLXNB1; 601053), and MET during invasive growth in epithelial cells. Binding of SEMA4D to PLXNB1 stimulated tyrosine kinase activity of MET, resulting in tyrosine phosphorylation of both receptors. This effect was not found in cells lacking MET expression.

Carrolo et al. (2003) demonstrated that wounding of hepatocytes by migration of sporozoites of the rodent malarial parasite Plasmodium berghei induced secretion of HGF, which rendered hepatocytes susceptible to infection. Infection depended on activation of the HGF receptor, MET, by secreted HGF. The malaria parasite exploited MET not as a primary binding site, but as a mediator of signals that made host cells susceptible to infection. HGF/MET signaling induced rearrangements of the host-cell actin cytoskeleton that were required for early development of parasites within hepatocytes.

Kaushansky and Kappe (2011) sought to determine if the mechanism of HGF induction by P. berghei described by Carrolo et al. (2003) applied to other Plasmodium species. They were able to reproduce the findings with P. berghei, but not with another rodent malaria parasite, P. yoelii, or with the human parasite, P. falciparum. Rodriguez and Mota (2011) concurred with the findings, but noted that the different rodent models remain useful in understanding the mechanisms underlying Plasmodium infection and contribute to future strategies to combat malaria.

Shen et al. (2000) found that the Listeria monocytogenes surface protein InIB promoted bacterial entry into mammalian cells by binding to the extracellular domain of MET. Treatment of cells with either InIB or whole Listeria cells induced rapid tyrosine phosphorylation of MET as well as 'scattering' of epithelial cells. MET-positive, but not MET-deficient, cell lines allowed entry of L. monocytogenes, indicating that MET is required for infection. Shen et al. (2000) concluded that InIB is a novel MET agonist that induces bacterial entry by exploitation of a host receptor tyrosine kinase pathway.

Veiga and Cossart (2005) found that L. monocytogenes InIB induced CBL (165360)-dependent monoubiquitination and endocytosis of MET and exploited the endocytosis to invade mammalian cells. In addition to MET, L. monocytogenes colocalized with EEA1 (605070), CBL, clathrin (see CLTC; 118955), and dynamin (see DNM1; 602377) during entry. Downregulation of CBL or RNA interference-mediated knockdown of major constituents of the endocytic machinery inhibited bacterial entry, indicating that the endocytic machinery is key to bacterial internalization.

The epidermal growth factor receptor (EGFR; 131550) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Engelman et al. (2007) described a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET (164860) protooncogene. Inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. Engelman et al. (2007) found that amplification of MET caused gefitinib resistance by driving ERBB3 (190151)-dependent activation of phosphoinositide 3-kinase, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, Engelman et al. (2007) proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

Zou et al. (2007) reported that the hepatocyte growth factor receptor MET plays an important part in preventing FAS (134637)-mediated apoptosis of hepatocytes by sequestering FAS. They also showed that FAS antagonism by MET is abrogated in human fatty liver disease. Through structure-function studies, the authors found that a YLGA amino acid motif located near the extracellular N terminus of the MET alpha subunit is necessary and sufficient to specifically bind the extracellular portion of FAS and to act as a potential FAS ligand (FASL; 134638) antagonist and inhibitor of FAS trimerization. Using mouse models of fatty liver disease, Zou et al. (2007) showed that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.

Rodgers et al. (2014) showed that the stem cell quiescent state is composed of 2 distinct functional phases, G0 and an 'alert' phase that they termed G-Alert. Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells, Rodgers et al. (2014) showed that mTORC1 (see 601231) activity is necessary and sufficient for the transition of satellite cells from G0 into G-Alert and that signaling through the HGF receptor c-Met is also necessary. Rodgers et al. (2014) also identified G0-to-G-Alert transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G-Alert possess enhanced tissue regenerative function. Rodgers et al. (2014) proposed that the transition of quiescent stem cells into G-Alert functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, thus priming them for cell cycle entry.

Finisguerra et al. (2015) showed that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand, hepatocyte growth factor (HGF; 142409). Met deletion in mouse neutrophils enhances tumor growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumor and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash, or peritonitis. Mechanistically, Met is induced by tumor-derived tumor necrosis factor-alpha (TNFA; 191160) or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase (NOS2; 163730) production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumor growth and metastasis. After systemic administration of a MET kinase inhibitor, Finisguerra et al. (2015) proved that the therapeutic benefit of MET targeting in cancer cells is partly countered by the protumoral effect arising from MET blockade in neutrophils. Finisguerra et al. (2015) concluded that their work identified an unprecedented role of MET in neutrophils, suggested a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supported the rationale for evaluating anti-MET drugs in certain inflammatory diseases.


Molecular Genetics

Papillary Renal Cell Carcinoma 1

Hereditary papillary renal carcinoma (RCCP1; 605074) is characterized by the development of multiple, bilateral papillary renal tumors. By linkage analysis, Schmidt et al. (1997) mapped an RCCP gene to 7q31.1-q34 in a 27-cM interval between D7S496 and D7S1837, the region containing the MET gene. Schmidt et al. (1997) found germline heterozygous missense mutations in the tyrosine kinase domain of the MET gene (164860.0001-164860.0005) in affected members of families and somatic mutations (see, e.g., 164860.0006) in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene were located in codons that are homologous to those in KIT (164920) and RET (164761), protooncogenes that are targets of naturally occurring mutations. Schmidt et al. (1997) suggested that missense mutations located in the MET protooncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.

Jeffers et al. (1997) introduced into MET cDNA mutations that had been identified in the gene in both hereditary and sporadic forms of papillary renal carcinoma and examined the effect of each mutation in biochemical and biologic assays. They found that the MET mutants exhibited increased levels of tyrosine phosphorylation and enhanced kinase activity toward an exogenous substrate when compared with wildtype MET. Moreover, NIH 3T3 cells expressing mutant MET molecules formed foci in vitro and were tumorigenic in nude mice. A strong correlation was found between the enzymatic and biologic activity of the mutants, suggesting that tumorigenesis by MET is quantitatively related to its level of activation. Jeffers et al. (1997) raised the possibility that activating MET mutations may contribute to other human malignancies.

MET is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. To investigate whether this oncogene is directly responsible for the acquisition of the metastatic phenotype, Giordano et al. (1997) exploited a single-hit oncogenic version of MET that was able to transform and to confer invasive and metastatic properties to nontumorigenic cells, both in vitro and in nude mice. They found a point mutation in the signal transducer docking site of MET that increased the transforming ability of the oncogene, but abolished its metastatic potential. They concluded that the metastatic potential of the MET oncogene relies on the properties of its multifunctional docking site, and that a single point mutation affecting signal transduction can dissociate neoplastic transformation from metastasis.

Tumors from patients with papillary renal carcinoma and germline mutations of MET commonly show trisomy of chromosome 7 when analyzed by cytogenetic studies and comparative genomic hybridization (CGH). Zhuang et al. (1998) studied 16 renal tumors from 2 patients with documented germline mutations in exon 16 of MET. Fluorescence in situ hybridization analysis showed trisomy 7 in all tumors. To determine whether it was the mutant or the wildtype MET gene that was duplicated, Zhuang et al. (1998) performed duplex PCR and phosphoimage densitometry using polymorphic microsatellite markers D7S1801 and D7S1822, which are linked to the disease gene locus, and D1S1646 as an internal control. They determined the parental origin of chromosome alleles by genotyping parental DNA. In all 16 tumors there was an increased signal intensity (2:1 ratio) of the microsatellite allele from a chromosome bearing the mutant MET compared with the allele from the chromosome bearing the wildtype MET. The study demonstrated a nonrandom duplication of the chromosome bearing the mutated MET in RCCP and implicated this event in tumorigenesis. The 2 patients from whom tumors were studied had the identical mutation: his1112 to arg (164860.0007).

Jeffers et al. (1998) studied the effect of mutationally activated MET in various cell types and as a transgene in mice. They showed that mutant MET induces motility of Madin-Darby canine kidney cells and metastasis of NIH 3T3 cells and that transgenic mice expressing the oncogenic form of MET may develop metastatic mammary carcinoma. An M1268T mutation of the MET gene was used in these studies.

Hepatocellular Carcinoma

Park et al. (1999) analyzed the tyrosine kinase domain (exons 15 to 19) of the MET gene in 75 primary liver cancers and identified 3 missense mutations (164860.0008-164860.0010) in 10 childhood hepatocellular carcinomas (HCC; 114550), whereas no mutations were detected in 16 adult HCCs, 21 cholangiocarcinomas, or 28 hepatoblastomas. Noting the very short incubation period from hepatitis B virus infection to the genesis of childhood HCC compared with adult HCC, Park et al. (1999) suggested that mutations of the tyrosine kinase domain of the MET gene may play such a role in the acceleration of the carcinogenesis in childhood HCC.

Autosomal Recessive Deafness 97

In a large consanguineous Pakistani family segregating autosomal recessive nonsyndromic deafness mapping to chromosome 7 (DFNB97; 616705), Mujtaba et al. (2015) performed whole-exome sequencing and identified a homozygous missense mutation in the MET gene (F841V; 164860.0012) that segregated fully with disease and was not found in 400 ethnically matched controls or exome databases. The authors noted that because only exonic regions were analyzed, it was possible that F841V represents a variant in linkage disequilibrium with the true pathogenic allele.

Susceptibility to Osteofibrous Dysplasia

In a 4-generation family segregating autosomal dominant osteofibrous dysplasia (OSFD; 607278), Gray et al. (2015) identified a heterozygous 26-bp deletion in the MET gene (164860.0013) that was present in 8 affected and 1 unaffected individual. In a second family with OSFD, another incompletely penetrant mutation in the MET gene was identified, a heterozygous splice site mutation (164860.0014) that was present in 5 affected and 4 unaffected family members. The same splice site mutation was detected in an affected mother and son from a third family, as well as in tissue from an unrelated female patient with OSFD. Both mutations involve the splice-donor consensus sequence for exon 14 and result in its exclusion from MET transcript. Analysis of 20 tissue samples from patients with sporadic unilateral OSFD revealed a somatic missense mutation (Y1003S) in 1 sample, also involving exon 14 of the MET gene. In transfected HEK293 cells, Gray et al. (2015) demonstrated that MET mutants involving deletion of exon 14 or the Y1003S mutation stabilize the MET receptor, resulting in a gain of function.

Distal Arthrogryposis Type 11

In 11 members of a 4-generation Chinese family with distal arthrogryposis type 11 (DA11; 620019), Zhou et al. (2019) identified a heterozygous missense mutation in the MET gene (Y1234C; 164860.0015). The mutation, which was identified by whole-exome sequencing, segregated with the disorder in the family. Transfection experiments in HEK293T cells showed that the mutant MET protein was unable to be phosphorylated after treatment with its ligand, hepatocyte growth factor. Zhou et al. (2019) concluded that the MET mutation impaired activation of the MET receptor.

Associations Pending Confirmation

For discussion of a possible association between variation in the MET gene and autism, see 164860.0011.


Animal Model

Maina et al. (1996) reported that hepatocyte growth factor and its receptor, the Met tyrosine kinase, are determinants of placenta, liver, and muscle development. They demonstrated that Met function in vivo requires signaling via 2 C-terminal tyrosines. Maina et al. (1996) demonstrated that mutation of both of these residues in the mouse genome caused embryonal death with placental liver and limb muscle defects, mimicking the phenotype of Met-null mutants. They disrupted the consensus sequences for Grb2 (108355) binding and reported that development proceeded to term without affecting placenta and liver but caused a striking reduction in limb muscle coupled to a generalized deficit of secondary fibers.

Maina et al. (2001) replaced the multifunctional docking sites of mouse Met with specific binding motifs for phosphatidylinositol-3 kinase (see 171833), Src tyrosine kinase (124095), or Grb2; they termed the mutants Met2P, Met2S, and Met2G, respectively. All 3 mutants retained normal signaling through the multiadaptor Gab1 (604439) but differentially recruited specific effectors. While Met2G mice developed normally, Met2P and Met2S mice were loss-of-function mutants displaying different phenotypes and rescue of distinct tissues. These data indicated that receptor tyrosine kinase-mediated activation of specific signaling pathways is required to fulfill cell-specific functions in vivo.

Boccaccio et al. (2005) developed a mouse model of sporadic tumorigenesis in which they targeted the activated human MET oncogene to adult liver. They observed slowly progressive hepatocarcinogenesis, which was preceded and accompanied by a disseminated intravascular coagulation (DIC)-like thrombohemorrhagic syndrome. Genomewide expression profiling of MLP29 cells transduced with the activated MET oncogene revealed prominent upregulation of plasminogen activator inhibitor-1 (PAI1; 173360) and cyclooxygenase-2 (PTGS2; 600262), and in vivo administration of a PAI1 or COX2 inhibitor slowed the evolution towards full-blown DIC. Boccaccio et al. (2005) concluded that this study provided the first direct genetic evidence for the link between oncogene activation and hemostasis.

Gray et al. (2015) studied preparations from whole dissected mouse embryonic limb buds collected at embryonic day (E) 10.5 and tibiae collected at E15, E17, and adult time points, and observed consistent but low-level expression of Met lacking the orthologous exon to human exon 14, which they designated Met(delta15). There was prominent expression of Met in chondrocytes and in the periosteum of long bones. RNA-seq analysis of E12.5 limb bud revealed the expression of both full-length and Met(delta15) isoforms in forelimbs and hindlimbs. RT-PCR of a proliferating cell population from 3-week-old mouse periosteum showed evidence for production of both full-length and Met(delta15) transcripts, suggesting that exon 15 splice exclusion is active in the periosteum during normal development. Using the mouse MC-3T3 preosteoblastic cell line, Gray et al. (2015) forced induction of the exon 15-exclusion event and observed retarded osteoblastic differentiation and inhibition of bone-matrix mineralization.

Using CRISPR/Cas9 editing, Zhou et al. (2019) generated a mouse model with a Y1232C mutation in the Met gene, corresponding to the human Y1234C mutation (164860.0015). Homozygosity for the mutation in mice caused embryonic lethality. At embryonic day 14.5 (E14.5) the homozygous embryos had a complete loss of muscle fibers in muscles that derive from migratory precursors, including limbs and diaphragm. Mice that were heterozygous for the mutation had a decreased number of muscle fibers at P0. At E16.5, the heterozygous mutant mice had decreased myofibers in the limbs compared to wildtype mice. Ki67 staining was reduced in the paraspinal muscles, demonstrating a defect in myoblast proliferation.


ALLELIC VARIANTS ( 15 Selected Examples):

.0001 RENAL CELL CARCINOMA, PAPILLARY, 1

MET, MET1149THR
  
RCV000014895...

In affected members of 2 families with hereditary papillary renal carcinoma (RCCP1; 605074), Schmidt et al. (1997) found a heterozygous germline 3640T-C transition in exon 17 of the MET gene that resulted in a met1149-to-thr (M1149T) amino acid substitution.


.0002 RENAL CELL CARCINOMA, PAPILLARY, 1

MET, VAL1206LEU
  
RCV000014896

In affected members of 2 families with hereditary papillary renal carcinoma (605074), Schmidt et al. (1997) found a heterozygous germline 3810G-T transversion in exon 18 of the MET gene that resulted in a val1206-to-leu (V1206L) amino acid substitution.


.0003 RENAL CELL CARCINOMA, PAPILLARY, 1

MET, VAL1238ILE
  
RCV000014897...

In affected members of 2 families with hereditary papillary renal carcinoma (605074), Schmidt et al. (1997) found a heterozygous germline 3906G-A transition in exon 19 of the MET gene that resulted in a val1238-to-ile (V1238I) amino acid substitution.


.0004 RENAL CELL CARCINOMA, PAPILLARY, 1

MET, ASP1246ASN
  
RCV000014898...

In affected members of 2 families with hereditary papillary renal carcinoma (605074), Schmidt et al. (1997) found a heterozygous germline 3930G-A transition in exon 19 of the MET gene that resulted in an asp1246-to-asn (D1246N) amino acid substitution.


.0005 RENAL CELL CARCINOMA, PAPILLARY, 1

MET, TYR1248CYS
  
RCV000014899...

In affected members of 2 families with hereditary papillary renal carcinoma (605074), Schmidt et al. (1997) found a heterozygous germline 3937G-A transition in exon 19 of the MET gene that resulted in a tyr1248-to-cys (Y1248C) amino acid substitution.


.0006 RENAL CELL CARCINOMA, PAPILLARY, 1, SOMATIC

MET, LEU1213VAL
  
RCV000014900

In a sporadic papillary renal carcinoma (605074), Schmidt et al. (1997) identified a 3831C-G transversion in exon 18 of the MET gene, resulting in a leu1213-to-val (L1213V) amino acid substitution.


.0007 RENAL CELL CARCINOMA, PAPILLARY, 1

MET, HIS1112ARG
  
RCV000014901...

In affected members of 2 families and in an unrelated individual, all with papillary renal carcinoma (605074), Schmidt et al. (1998) detected a germline heterozygous A-to-G transition at nucleotide 3529 in exon 16 of the MET gene. The mutation resulted in a his1112-to-arg (H1112R) substitution in the tyrosine kinase domain of the protein. Haplotype analysis suggested that a founder effect was responsible for the disorder in the 2 families.

In tumors from 2 patients from the 2 families described by Schmidt et al. (1998), Zhuang et al. (1998) showed duplication of the mutant MET allele. One patient was asymptomatic but had been examined by CT scan at age 44 because of family history of renal cancer. Multiple tumor nodules were found in both kidneys. The second patient was a member of the second family with 13 affected members, 4 of whom were asymptomatic and identified as having renal tumors by CT scan. This patient had multiple, bilateral papillary renal tumors and had undergone unilateral nephrectomy.


.0008 HEPATOCELLULAR CARCINOMA, CHILDHOOD TYPE, SOMATIC

MET, THR1191ILE
  
RCV000014902

In a study of 75 primary liver cancers, Park et al. (1999) identified 3 missense mutations within the tyrosine kinase domain of the MET gene in 10 childhood hepatocellular carcinomas (HCC; 114550), while no mutations were detected in 16 adult HCCs, 21 cholangiocarcinomas, or 28 hepatoblastomas. The sequencing analysis of the MET gene was limited to the tyrosine kinase domain (exons 15 to 19). One mutation was a change of codon 1191 in exon 17 from ACT (thr) to ATT (ile). A second mutation was a change of codon 1268 in exon 19 from ATG (met) to ATA (ile) (164860.0009). The third mutation was a change of codon 1262 in exon 19 from AAG (lys) to AGG (arg) (164860.0010). The very short incubation period from hepatitis B virus infection to the genesis of childhood HCC as compared with adult HCC suggests that there may be an additional mechanism that accelerates the carcinogenesis of childhood HCC. Park et al. (1999) suggested that mutations of the tyrosine kinase domain of the MET gene may play such a role in the acceleration of the carcinogenesis in childhood HCC.


.0009 HEPATOCELLULAR CARCINOMA, CHILDHOOD TYPE, SOMATIC

MET, MET1268ILE
  
RCV000014903...

.0010 HEPATOCELLULAR CARCINOMA, CHILDHOOD TYPE, SOMATIC

MET, LYS1262ARG
  
RCV000014904

.0011 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

MET, -20G-C (rs1858830)
  
RCV000014905

This variant, formerly titled AUTISM, ASSOCIATION WITH, 9, has been reclassified as a variant of unknown significance because its contribution to autism (see 611015) has not been confirmed.

Campbell et al. (2006) identified a G-C transversion (rs1858830) in the promoter of the MET gene, located 20 basepairs 5-prime to the transcriptional start site. In vitro functional expression studies showed that the C allele resulted in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. In 204 families with autism, Campbell et al. (2006) found a significant association between autism and the -20C allele. The association was confirmed in a replication study of 539 additional autistic families and in the combined sample. Multiplex families, in which more than 1 child has autism, exhibited the strongest allelic association (p = 0.000007). In case-control analysis, the relative risk for autism was 2.27 for the CC genotype and 1.67 for the GC genotype compared to the GG genotype. No functional studies were performed.


.0012 DEAFNESS, AUTOSOMAL RECESSIVE 97 (1 family)

MET, PHE841VAL
  
RCV000185580...

In 9 affected members of a large consanguineous Pakistani family (HLGM17) segregating autosomal recessive nonsyndromic deafness (DFNB97; 616705), Mujtaba et al. (2015) identified homozygosity for a c.2521T-G transversion (c.2521T-G, NM_000245.2) in exon 11 of the MET gene, resulting in a phe841-to-val (F841V) substitution at a highly conserved residue within the IPT4 domain. The mutation segregated fully with disease in the family and was not found in 400 Pakistani controls or in the Exome Variant Server, ExAC, or 1000 Genomes Project databases. The authors noted that because only exonic regions were analyzed, it was possible that F841V represents a variant in linkage disequilibrium with the true pathogenic allele.


.0013 OSTEOFIBROUS DYSPLASIA, SUSCEPTIBILITY TO

MET, 26-BP DEL, NT3010
  
RCV000210883

In 8 affected individuals from a 4-generation family with osteofibrous dysplasia (OSFD; 607278), originally reported by Beals and Fraser (1976), Gray et al. (2015) identified heterozygosity for a 26-bp deletion in the MET gene (c.3010_3028+8del, NM_000245.2) (Leu964_Asp1010del) that includes the donor splice site at the exon 14/intron 14 junction. The deletion was also present in 1 unaffected family member, but was not found in the Exome Variant Server or dbSNP build 131 databases. RT-PCR of cultured patient dermal fibroblasts showed that the deletion results in exclusion of exon 14 from the mature MET transcript, predicting the in-frame omission of the phylogenetically conserved juxtamembrane domain of the MET receptor. In transfected HEK293 cells, Gray et al. (2015) demonstrated that MET mutants involving deletion of exon 14 stabilize the MET receptor, resulting in a gain of function.


.0014 OSTEOFIBROUS DYSPLASIA, SUSCEPTIBILITY TO

MET, IVS14, G-T, +1
  
RCV000210870...

In a family with osteofibrous dysplasia (OSFD; 607278) that was previously studied by Karol et al. (2005), Gray et al. (2015) identified a heterozygous splice site mutation in intron 14 of the MET gene (c.3028+1G-T, NM_000245.2) (Leu964_Asp1010del) that was present in 5 affected and 4 unaffected family members. The same splice site mutation was detected in an affected mother and son from a second family, as well as in normal tissue adjacent to an excised lesion from an unrelated female patient with OSFD, who was originally reported by Sunkara et al. (1997). RT-PCR on lymphoblastoid cell lines from the first family and excised lesional bone tissue from the second family showed that the splice site mutation results in exclusion of exon 14 from mature MET transcript, predicting the in-frame omission of the phylogenetically conserved juxtamembrane domain of the MET receptor. In transfected HEK293 cells, Gray et al. (2015) demonstrated that MET mutants involving deletion of exon 14 stabilize the MET receptor, resulting in a gain of function.


.0015 ARTHROGRYPOSIS, DISTAL, TYPE 11 (1 family)

MET, TYR1234CYS
  
RCV000626485...

In 11 members of a Chinese family with distal arthrogryposis type 11 (DA11; 620019), Zhou et al. (2019) identified heterozygosity for a c.3701A-G transition (c.3701A-G, NM_000245.2) in the MET gene, resulting in a tyr1234-to-cys (Y1234C) substitution. The mutation was identified by whole-exome sequencing and segregated with the disorder in the family. Transfection studies in HEK293T cells showed that the mutant MET protein was unable to be phosphorylated after treatment with human hepatocyte growth factor.


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  10. Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., Kosaka, T., Holmes, A. J., Rogers, A. M., Cappuzzo, F., Mok, T., Lee, C., Johnson, B. E., Cantley, L. C., Janne, P. A. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316: 1039-1043, 2007. [PubMed: 17463250, related citations] [Full Text]

  11. Finisguerra, V., Di Conza, G., Di Matteo, M., Serneels, J., Costa, S., Thompson, A. A. R., Wauters, E., Walmsley, S., Prenen, H., Granot, Z., Casazza, A., Mazzone, M. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522: 349-353, 2015. [PubMed: 25985180, images, related citations] [Full Text]

  12. Giordano, S., Bardelli, A., Zhen, Z., Menard, S., Ponzetto, C., Comoglio, P. M. A point mutation in the MET oncogene abrogates metastasis without affecting transformation. Proc. Nat. Acad. Sci. 94: 13868-13872, 1997. [PubMed: 9391119, images, related citations] [Full Text]

  13. Giordano, S., Corso, S., Conrotto, P., Artigiani, S., Gilestro, G., Barberis, D., Tamagnone, L., Comoglio, P. M. The Semaphorin 4D receptor controls invasive growth by coupling with Met. Nature Cell Biol. 4: 720-724, 2002. [PubMed: 12198496, related citations] [Full Text]

  14. Gray, M. J., Kannu, P., Sharma, A., Neyt, C., Zhang, D., Paria, N., Daniel, P. B., Whetstone, H., Sprenger, H.-G., Hammerschmidt, P., Weng, A., Dupuis, L., and 20 others. Mutations preventing regulated exon skipping in MET cause osteofibrous dysplasia. Am. J. Hum. Genet. 97: 837-847, 2015. [PubMed: 26637977, images, related citations] [Full Text]

  15. Jeffers, M., Fiscella, M., Webb, C. P., Anver, M., Koochekpour, S., Vande Woude, G. F. The mutationally activated Met receptor mediates motility and metastasis. Proc. Nat. Acad. Sci. 95: 14417-14422, 1998. [PubMed: 9826715, images, related citations] [Full Text]

  16. Jeffers, M., Schmidt, L., Nakaigawa, N., Webb, C. P., Weirich, G., Kishida, T., Zbar, B., Vande Woude, G. F. Activating mutations for the Met tyrosine receptor in human cancer. Proc. Nat. Acad. Sci. 94: 11445-11450, 1997. [PubMed: 9326629, images, related citations] [Full Text]

  17. Karol, L. A., Brown, D. S., Wise, C. A., Waldron, M. Familial osteofibrous dysplasia: a case series. J. Bone Joint Surg. Am. 87: 2297-2307, 2005. [PubMed: 16203897, related citations] [Full Text]

  18. Kaushansky, A., Kappe, S. H. I. The crucial role of hepatocyte growth factor receptor during liver-stage infection is not conserved among Plasmodium species. (Letter) Nature Med. 17: 1180-1181, 2011. [PubMed: 21988987, related citations] [Full Text]

  19. Maina, F., Casagranda, F., Audero, E., Simeone, A., Comoglio, P. M., Klein, R., Ponzetto, C. Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development. Cell 87: 531-542, 1996. [PubMed: 8898205, related citations] [Full Text]

  20. Maina, F., Pante, G., Helmbacher, F., Andres, R., Porthin, A., Davies, A. M., Ponzetto, C., Klein, R. Coupling Met to specific pathways results in distinct developmental outcomes. Molec. Cell 7: 1293-1306, 2001. [PubMed: 11430831, related citations] [Full Text]

  21. Mujtaba, G., Schultz, J. M., Imtiaz, A., Morell, R. J., Friedman, T. B., Naz, S. A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss. J. Med. Genet. 52: 548-552, 2015. [PubMed: 25941349, images, related citations] [Full Text]

  22. Park, M., Dean, M., Kaul, K., Braun, M. J., Gonda, M. A., Vande Woude, G. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc. Nat. Acad. Sci. 84: 6379-6383, 1987. [PubMed: 2819873, related citations] [Full Text]

  23. Park, W. S., Dong, S. M., Kim, S. Y., Na, E. Y., Shin, M. S., Pi, J. H., Kim, B. J., Bae, J. H., Hong, Y. K., Lee, K. S., Lee, S. H., Yoo, N. J., Jang, J. J., Pack, S., Zhuang, Z., Schmidt, L., Zbar, B., Lee, J. Y. Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res. 59: 307-310, 1999. [PubMed: 9927037, related citations]

  24. Powell, E. M., Mars, W. M., Levitt, P. Hepatocyte growth factor/scatter factor is a motogen for interneurons migrating from the ventral to dorsal telencephalon. Neuron 30: 79-89, 2001. [PubMed: 11343646, related citations] [Full Text]

  25. Rodgers, J. T., King, K. Y., Brett, J. O., Cromie, M. J., Charville, G. W., Maguire, K. K., Brunson, C., Mastey, N., Liu, L., Tsai, C.-R., Goodell, M. A., Rando, T. A. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G-Alert. Nature 510: 393-396, 2014. [PubMed: 24870234, images, related citations] [Full Text]

  26. Rodriguez, A., Mota, M. M. Reply to Kaushansky and Kappe. (Letter) Nature Med. 17: 1181 only, 2011.

  27. Schmidt, L., Duh, F.-M., Chen, F., Kishida, T., Glenn, G., Choyke, P., Scherer, S. W., Zhuang, Z., Lubensky, I., Dean, M., Allikmets, R., Chidambaram, A., and 23 others. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinoma. Nature Genet. 16: 68-73, 1997. [PubMed: 9140397, related citations] [Full Text]

  28. Schmidt, L., Junker, K., Weirich, G., Glenn, G., Choyke, P., Lubensky, I., Zhuang, Z., Jeffers, M., Vande Woude, G., Neumann, H., Walther, M., Linehan, W. M., Zbar, B. Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res. 58: 1719-1722, 1998. [PubMed: 9563489, related citations]

  29. Shen, Y., Naujokas, M., Park, M., Ireton, K. InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell 103: 501-510, 2000. [PubMed: 11081636, related citations] [Full Text]

  30. Sunkara, U. K., Sponseller, P. D., Miller, N. H., McCarthy, E. F. Bilateral osteofibrous dysplasia: a report of two cases and review of the literature. Iowa Orthop. J. 17: 47-52, 1997. [PubMed: 9234973, related citations]

  31. Veiga, E., Cossart, P. Listeria hijacks the clathrin-dependent endocytic machinery to invade mammalian cells. Nature Cell Biol. 7: 894-900, 2005. [PubMed: 16113677, related citations] [Full Text]

  32. Zhou, H., Lian, C., Wang, T., Yang, X., Xu, C., Su, D., Zheng, S., Huang, X., Liao, Z., Zhou, T., Qiu, X., Chen, Y., Gao, B., Li, Y., Wang, X., You, G., Fu, Q., Gurnett, C., Huang, D., Su, P. MET mutation causes muscular dysplasia and arthrogryposis. EMBO Molec. Med. 11: e9709, 2019. [PubMed: 30777867, images, related citations] [Full Text]

  33. Zhuang, Z., Park, W.-S., Pack, S., Schmidt, L., Vortmeyer, A. O., Pak, E., Pham, T., Weil, R. J., Candidus, S., Lubensky, I. A., Linehan, W. M., Zbar, B., Weirich, G. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nature Genet. 20: 66-69, 1998. [PubMed: 9731534, related citations] [Full Text]

  34. Zou, C., Ma, J., Wang, X., Guo, L., Zhu, Z., Stoops, J., Eaker, A. E., Johnson, C. J., Strom, S., Michalopoulos, G. K., DeFrances, M. C., Zarnegar, R. Lack of Fas antagonism by Met in human fatty liver disease. Nature Med. 13: 1078-1085, 2007. [PubMed: 17704785, related citations] [Full Text]


Hilary J. Vernon - updated : 08/25/2022
Marla J. F. O'Neill - updated : 04/12/2016
Marla J. F. O'Neill - updated : 12/18/2015
Ada Hamosh - updated : 10/15/2015
Ada Hamosh - updated : 7/15/2014
Paul J. Converse - updated : 10/20/2011
Ada Hamosh - updated : 3/26/2008
Ada Hamosh - updated : 6/14/2007
Cassandra L. Kniffin - updated : 1/4/2007
Paul J. Converse - updated : 10/18/2005
Marla J. F. O'Neill - updated : 3/23/2005
Ada Hamosh - updated : 10/29/2003
Patricia A. Hartz - updated : 10/28/2002
Dawn Watkins-Chow - updated : 6/12/2002
Stylianos E. Antonarakis - updated : 7/3/2001
Victor A. McKusick - updated : 3/21/2000
Victor A. McKusick - updated : 3/24/1999
Victor A. McKusick - updated : 12/10/1998
Victor A. McKusick - updated : 8/28/1998
Victor A. McKusick - updated : 1/13/1998
Victor A. McKusick - updated : 11/6/1997
Victor A. McKusick - updated : 4/30/1997
Moyra Smith - updated : 12/13/1996
Creation Date:
Victor A. McKusick : 6/2/1986
carol : 08/25/2022
carol : 01/23/2020
carol : 08/23/2016
alopez : 04/12/2016
carol : 12/18/2015
alopez : 10/15/2015
carol : 2/16/2015
alopez : 7/15/2014
carol : 11/14/2013
mgross : 10/7/2013
mgross : 10/20/2011
mgross : 10/20/2011
carol : 9/15/2011
ckniffin : 9/13/2011
alopez : 4/5/2010
ckniffin : 11/17/2009
alopez : 3/27/2008
alopez : 3/27/2008
terry : 3/26/2008
alopez : 6/28/2007
terry : 6/14/2007
ckniffin : 5/16/2007
carol : 5/14/2007
ckniffin : 5/10/2007
ckniffin : 3/12/2007
wwang : 1/25/2007
ckniffin : 1/4/2007
mgross : 10/18/2005
alopez : 3/23/2005
alopez : 3/23/2005
alopez : 11/7/2003
alopez : 10/29/2003
terry : 10/29/2003
mgross : 10/28/2002
mgross : 10/28/2002
cwells : 6/12/2002
mgross : 7/3/2001
carol : 7/20/2000
terry : 3/21/2000
carol : 9/20/1999
mgross : 4/2/1999
mgross : 3/30/1999
terry : 3/24/1999
carol : 12/15/1998
carol : 12/15/1998
terry : 12/10/1998
alopez : 8/31/1998
terry : 8/28/1998
carol : 3/28/1998
alopez : 1/13/1998
dholmes : 12/24/1997
jenny : 11/12/1997
terry : 11/6/1997
alopez : 8/8/1997
alopez : 5/13/1997
mark : 4/30/1997
terry : 4/30/1997
jenny : 12/23/1996
mark : 12/13/1996
jenny : 12/12/1996
mark : 12/9/1996
mark : 6/9/1996
carol : 1/6/1993
supermim : 3/16/1992
carol : 3/4/1991
carol : 2/28/1991
supermim : 3/20/1990
supermim : 1/13/1990

* 164860

MET PROTOONCOGENE, RECEPTOR TYROSINE KINASE; MET


Alternative titles; symbols

MET PROTOONCOGENE
ONCOGENE MET
HEPATOCYTE GROWTH FACTOR RECEPTOR; HGFR


HGNC Approved Gene Symbol: MET

Cytogenetic location: 7q31.2     Genomic coordinates (GRCh38): 7:116,672,196-116,798,377 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q31.2 ?Arthrogryposis, distal, type 11 620019 Autosomal dominant 3
?Deafness, autosomal recessive 97 616705 Autosomal recessive 3
{Osteofibrous dysplasia, susceptibility to} 607278 Autosomal dominant 3
Hepatocellular carcinoma, childhood type, somatic 114550 3
Renal cell carcinoma, papillary, 1, familial and somatic 605074 3

TEXT

Cloning and Expression

Cooper et al. (1984) cloned a transforming gene from a chemically transformed human osteosarcoma-derived cell line and mapped it to 7p11.4-qter. Identity to all previously known oncogenes except ERBB (131550) was ruled out by the fact that they are encoded by other chromosomes; identity to ERBB is probably excluded by failure of direct hybridizations of the 2 probes. MET was the designation suggested by Cooper et al. (1984).

Dean et al. (1985) showed that MET is in the tyrosine kinase family of oncogenes. It appeared to be most closely related in sequence to the human insulin receptor and ABL oncogene.

From the sequence of MET cDNA, Park et al. (1987) concluded that this oncogene is a cell-surface receptor for a then unknown ligand. The c-Met protooncogene product is a receptor-like tyrosine kinase composed of disulfide-linked subunits of 50 kD (alpha) and 145 kD (beta). In the fully processed c-Met product, the alpha subunit is extracellular, and the beta subunit has extracellular, transmembrane, and tyrosine kinase domains as well as sites of tyrosine phosphorylation.

By immunohistochemical staining and Western blot analysis in lesional tissue from affected members of 2 unrelated families with osteofibrous dysplasia (607278; see MOLECULAR GENETICS), Gray et al. (2015) demonstrated the presence of MET in both osteoblasts and osteoclasts. An assay on metaphyseal bone obtained from an age-matched healthy individual also showed detectable levels of MET.


Mapping

By in situ hybridization, Dean et al. (1985) assigned the MET gene to 7q21-q31, where it is tightly linked to CF (219700) which is thought to be located in the proximal part of 7q22. It is about 10 cM from TCRB (see 186930) and is in a region that is associated with nonrandom chromosomal deletions in some patients with acute nonlymphocytic leukemia.

Dean et al. (1987) demonstrated that the Met oncogene is located on chromosome 6 in the mouse, where it is tightly linked to an obesity mutation ('ob').


Gene Function

Bottaro et al. (1991) demonstrated that the beta-subunit of the c-Met protooncogene product is the cell-surface receptor for hepatocyte growth factor (HGF; 142409).

Cooper (1992) reviewed the development of understanding of the MET oncogene in an article subtitled 'From detection by transfection to transmembrane receptor for hepatocyte growth factor.'

Using in situ hybridization and immunoblotting, Powell et al. (2001) detected expression of HGF and MET in the cerebral wall and ganglionic eminence of the developing mouse forebrain. Using scatter assays, Powell et al. (2001) concluded that motogenic activity in the forebrain is due to HGF.

Giordano et al. (2002) presented evidence for cross-talk between the semaphorin 4D (SEMA4D; 601866) receptor, plexin B1 (PLXNB1; 601053), and MET during invasive growth in epithelial cells. Binding of SEMA4D to PLXNB1 stimulated tyrosine kinase activity of MET, resulting in tyrosine phosphorylation of both receptors. This effect was not found in cells lacking MET expression.

Carrolo et al. (2003) demonstrated that wounding of hepatocytes by migration of sporozoites of the rodent malarial parasite Plasmodium berghei induced secretion of HGF, which rendered hepatocytes susceptible to infection. Infection depended on activation of the HGF receptor, MET, by secreted HGF. The malaria parasite exploited MET not as a primary binding site, but as a mediator of signals that made host cells susceptible to infection. HGF/MET signaling induced rearrangements of the host-cell actin cytoskeleton that were required for early development of parasites within hepatocytes.

Kaushansky and Kappe (2011) sought to determine if the mechanism of HGF induction by P. berghei described by Carrolo et al. (2003) applied to other Plasmodium species. They were able to reproduce the findings with P. berghei, but not with another rodent malaria parasite, P. yoelii, or with the human parasite, P. falciparum. Rodriguez and Mota (2011) concurred with the findings, but noted that the different rodent models remain useful in understanding the mechanisms underlying Plasmodium infection and contribute to future strategies to combat malaria.

Shen et al. (2000) found that the Listeria monocytogenes surface protein InIB promoted bacterial entry into mammalian cells by binding to the extracellular domain of MET. Treatment of cells with either InIB or whole Listeria cells induced rapid tyrosine phosphorylation of MET as well as 'scattering' of epithelial cells. MET-positive, but not MET-deficient, cell lines allowed entry of L. monocytogenes, indicating that MET is required for infection. Shen et al. (2000) concluded that InIB is a novel MET agonist that induces bacterial entry by exploitation of a host receptor tyrosine kinase pathway.

Veiga and Cossart (2005) found that L. monocytogenes InIB induced CBL (165360)-dependent monoubiquitination and endocytosis of MET and exploited the endocytosis to invade mammalian cells. In addition to MET, L. monocytogenes colocalized with EEA1 (605070), CBL, clathrin (see CLTC; 118955), and dynamin (see DNM1; 602377) during entry. Downregulation of CBL or RNA interference-mediated knockdown of major constituents of the endocytic machinery inhibited bacterial entry, indicating that the endocytic machinery is key to bacterial internalization.

The epidermal growth factor receptor (EGFR; 131550) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Engelman et al. (2007) described a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET (164860) protooncogene. Inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. Engelman et al. (2007) found that amplification of MET caused gefitinib resistance by driving ERBB3 (190151)-dependent activation of phosphoinositide 3-kinase, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, Engelman et al. (2007) proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

Zou et al. (2007) reported that the hepatocyte growth factor receptor MET plays an important part in preventing FAS (134637)-mediated apoptosis of hepatocytes by sequestering FAS. They also showed that FAS antagonism by MET is abrogated in human fatty liver disease. Through structure-function studies, the authors found that a YLGA amino acid motif located near the extracellular N terminus of the MET alpha subunit is necessary and sufficient to specifically bind the extracellular portion of FAS and to act as a potential FAS ligand (FASL; 134638) antagonist and inhibitor of FAS trimerization. Using mouse models of fatty liver disease, Zou et al. (2007) showed that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.

Rodgers et al. (2014) showed that the stem cell quiescent state is composed of 2 distinct functional phases, G0 and an 'alert' phase that they termed G-Alert. Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells, Rodgers et al. (2014) showed that mTORC1 (see 601231) activity is necessary and sufficient for the transition of satellite cells from G0 into G-Alert and that signaling through the HGF receptor c-Met is also necessary. Rodgers et al. (2014) also identified G0-to-G-Alert transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G-Alert possess enhanced tissue regenerative function. Rodgers et al. (2014) proposed that the transition of quiescent stem cells into G-Alert functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, thus priming them for cell cycle entry.

Finisguerra et al. (2015) showed that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand, hepatocyte growth factor (HGF; 142409). Met deletion in mouse neutrophils enhances tumor growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumor and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash, or peritonitis. Mechanistically, Met is induced by tumor-derived tumor necrosis factor-alpha (TNFA; 191160) or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase (NOS2; 163730) production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumor growth and metastasis. After systemic administration of a MET kinase inhibitor, Finisguerra et al. (2015) proved that the therapeutic benefit of MET targeting in cancer cells is partly countered by the protumoral effect arising from MET blockade in neutrophils. Finisguerra et al. (2015) concluded that their work identified an unprecedented role of MET in neutrophils, suggested a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supported the rationale for evaluating anti-MET drugs in certain inflammatory diseases.


Molecular Genetics

Papillary Renal Cell Carcinoma 1

Hereditary papillary renal carcinoma (RCCP1; 605074) is characterized by the development of multiple, bilateral papillary renal tumors. By linkage analysis, Schmidt et al. (1997) mapped an RCCP gene to 7q31.1-q34 in a 27-cM interval between D7S496 and D7S1837, the region containing the MET gene. Schmidt et al. (1997) found germline heterozygous missense mutations in the tyrosine kinase domain of the MET gene (164860.0001-164860.0005) in affected members of families and somatic mutations (see, e.g., 164860.0006) in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene were located in codons that are homologous to those in KIT (164920) and RET (164761), protooncogenes that are targets of naturally occurring mutations. Schmidt et al. (1997) suggested that missense mutations located in the MET protooncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.

Jeffers et al. (1997) introduced into MET cDNA mutations that had been identified in the gene in both hereditary and sporadic forms of papillary renal carcinoma and examined the effect of each mutation in biochemical and biologic assays. They found that the MET mutants exhibited increased levels of tyrosine phosphorylation and enhanced kinase activity toward an exogenous substrate when compared with wildtype MET. Moreover, NIH 3T3 cells expressing mutant MET molecules formed foci in vitro and were tumorigenic in nude mice. A strong correlation was found between the enzymatic and biologic activity of the mutants, suggesting that tumorigenesis by MET is quantitatively related to its level of activation. Jeffers et al. (1997) raised the possibility that activating MET mutations may contribute to other human malignancies.

MET is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. To investigate whether this oncogene is directly responsible for the acquisition of the metastatic phenotype, Giordano et al. (1997) exploited a single-hit oncogenic version of MET that was able to transform and to confer invasive and metastatic properties to nontumorigenic cells, both in vitro and in nude mice. They found a point mutation in the signal transducer docking site of MET that increased the transforming ability of the oncogene, but abolished its metastatic potential. They concluded that the metastatic potential of the MET oncogene relies on the properties of its multifunctional docking site, and that a single point mutation affecting signal transduction can dissociate neoplastic transformation from metastasis.

Tumors from patients with papillary renal carcinoma and germline mutations of MET commonly show trisomy of chromosome 7 when analyzed by cytogenetic studies and comparative genomic hybridization (CGH). Zhuang et al. (1998) studied 16 renal tumors from 2 patients with documented germline mutations in exon 16 of MET. Fluorescence in situ hybridization analysis showed trisomy 7 in all tumors. To determine whether it was the mutant or the wildtype MET gene that was duplicated, Zhuang et al. (1998) performed duplex PCR and phosphoimage densitometry using polymorphic microsatellite markers D7S1801 and D7S1822, which are linked to the disease gene locus, and D1S1646 as an internal control. They determined the parental origin of chromosome alleles by genotyping parental DNA. In all 16 tumors there was an increased signal intensity (2:1 ratio) of the microsatellite allele from a chromosome bearing the mutant MET compared with the allele from the chromosome bearing the wildtype MET. The study demonstrated a nonrandom duplication of the chromosome bearing the mutated MET in RCCP and implicated this event in tumorigenesis. The 2 patients from whom tumors were studied had the identical mutation: his1112 to arg (164860.0007).

Jeffers et al. (1998) studied the effect of mutationally activated MET in various cell types and as a transgene in mice. They showed that mutant MET induces motility of Madin-Darby canine kidney cells and metastasis of NIH 3T3 cells and that transgenic mice expressing the oncogenic form of MET may develop metastatic mammary carcinoma. An M1268T mutation of the MET gene was used in these studies.

Hepatocellular Carcinoma

Park et al. (1999) analyzed the tyrosine kinase domain (exons 15 to 19) of the MET gene in 75 primary liver cancers and identified 3 missense mutations (164860.0008-164860.0010) in 10 childhood hepatocellular carcinomas (HCC; 114550), whereas no mutations were detected in 16 adult HCCs, 21 cholangiocarcinomas, or 28 hepatoblastomas. Noting the very short incubation period from hepatitis B virus infection to the genesis of childhood HCC compared with adult HCC, Park et al. (1999) suggested that mutations of the tyrosine kinase domain of the MET gene may play such a role in the acceleration of the carcinogenesis in childhood HCC.

Autosomal Recessive Deafness 97

In a large consanguineous Pakistani family segregating autosomal recessive nonsyndromic deafness mapping to chromosome 7 (DFNB97; 616705), Mujtaba et al. (2015) performed whole-exome sequencing and identified a homozygous missense mutation in the MET gene (F841V; 164860.0012) that segregated fully with disease and was not found in 400 ethnically matched controls or exome databases. The authors noted that because only exonic regions were analyzed, it was possible that F841V represents a variant in linkage disequilibrium with the true pathogenic allele.

Susceptibility to Osteofibrous Dysplasia

In a 4-generation family segregating autosomal dominant osteofibrous dysplasia (OSFD; 607278), Gray et al. (2015) identified a heterozygous 26-bp deletion in the MET gene (164860.0013) that was present in 8 affected and 1 unaffected individual. In a second family with OSFD, another incompletely penetrant mutation in the MET gene was identified, a heterozygous splice site mutation (164860.0014) that was present in 5 affected and 4 unaffected family members. The same splice site mutation was detected in an affected mother and son from a third family, as well as in tissue from an unrelated female patient with OSFD. Both mutations involve the splice-donor consensus sequence for exon 14 and result in its exclusion from MET transcript. Analysis of 20 tissue samples from patients with sporadic unilateral OSFD revealed a somatic missense mutation (Y1003S) in 1 sample, also involving exon 14 of the MET gene. In transfected HEK293 cells, Gray et al. (2015) demonstrated that MET mutants involving deletion of exon 14 or the Y1003S mutation stabilize the MET receptor, resulting in a gain of function.

Distal Arthrogryposis Type 11

In 11 members of a 4-generation Chinese family with distal arthrogryposis type 11 (DA11; 620019), Zhou et al. (2019) identified a heterozygous missense mutation in the MET gene (Y1234C; 164860.0015). The mutation, which was identified by whole-exome sequencing, segregated with the disorder in the family. Transfection experiments in HEK293T cells showed that the mutant MET protein was unable to be phosphorylated after treatment with its ligand, hepatocyte growth factor. Zhou et al. (2019) concluded that the MET mutation impaired activation of the MET receptor.

Associations Pending Confirmation

For discussion of a possible association between variation in the MET gene and autism, see 164860.0011.


Animal Model

Maina et al. (1996) reported that hepatocyte growth factor and its receptor, the Met tyrosine kinase, are determinants of placenta, liver, and muscle development. They demonstrated that Met function in vivo requires signaling via 2 C-terminal tyrosines. Maina et al. (1996) demonstrated that mutation of both of these residues in the mouse genome caused embryonal death with placental liver and limb muscle defects, mimicking the phenotype of Met-null mutants. They disrupted the consensus sequences for Grb2 (108355) binding and reported that development proceeded to term without affecting placenta and liver but caused a striking reduction in limb muscle coupled to a generalized deficit of secondary fibers.

Maina et al. (2001) replaced the multifunctional docking sites of mouse Met with specific binding motifs for phosphatidylinositol-3 kinase (see 171833), Src tyrosine kinase (124095), or Grb2; they termed the mutants Met2P, Met2S, and Met2G, respectively. All 3 mutants retained normal signaling through the multiadaptor Gab1 (604439) but differentially recruited specific effectors. While Met2G mice developed normally, Met2P and Met2S mice were loss-of-function mutants displaying different phenotypes and rescue of distinct tissues. These data indicated that receptor tyrosine kinase-mediated activation of specific signaling pathways is required to fulfill cell-specific functions in vivo.

Boccaccio et al. (2005) developed a mouse model of sporadic tumorigenesis in which they targeted the activated human MET oncogene to adult liver. They observed slowly progressive hepatocarcinogenesis, which was preceded and accompanied by a disseminated intravascular coagulation (DIC)-like thrombohemorrhagic syndrome. Genomewide expression profiling of MLP29 cells transduced with the activated MET oncogene revealed prominent upregulation of plasminogen activator inhibitor-1 (PAI1; 173360) and cyclooxygenase-2 (PTGS2; 600262), and in vivo administration of a PAI1 or COX2 inhibitor slowed the evolution towards full-blown DIC. Boccaccio et al. (2005) concluded that this study provided the first direct genetic evidence for the link between oncogene activation and hemostasis.

Gray et al. (2015) studied preparations from whole dissected mouse embryonic limb buds collected at embryonic day (E) 10.5 and tibiae collected at E15, E17, and adult time points, and observed consistent but low-level expression of Met lacking the orthologous exon to human exon 14, which they designated Met(delta15). There was prominent expression of Met in chondrocytes and in the periosteum of long bones. RNA-seq analysis of E12.5 limb bud revealed the expression of both full-length and Met(delta15) isoforms in forelimbs and hindlimbs. RT-PCR of a proliferating cell population from 3-week-old mouse periosteum showed evidence for production of both full-length and Met(delta15) transcripts, suggesting that exon 15 splice exclusion is active in the periosteum during normal development. Using the mouse MC-3T3 preosteoblastic cell line, Gray et al. (2015) forced induction of the exon 15-exclusion event and observed retarded osteoblastic differentiation and inhibition of bone-matrix mineralization.

Using CRISPR/Cas9 editing, Zhou et al. (2019) generated a mouse model with a Y1232C mutation in the Met gene, corresponding to the human Y1234C mutation (164860.0015). Homozygosity for the mutation in mice caused embryonic lethality. At embryonic day 14.5 (E14.5) the homozygous embryos had a complete loss of muscle fibers in muscles that derive from migratory precursors, including limbs and diaphragm. Mice that were heterozygous for the mutation had a decreased number of muscle fibers at P0. At E16.5, the heterozygous mutant mice had decreased myofibers in the limbs compared to wildtype mice. Ki67 staining was reduced in the paraspinal muscles, demonstrating a defect in myoblast proliferation.


ALLELIC VARIANTS 15 Selected Examples):

.0001   RENAL CELL CARCINOMA, PAPILLARY, 1

MET, MET1149THR
SNP: rs121913668, ClinVar: RCV000014895, RCV000565834, RCV002228027

In affected members of 2 families with hereditary papillary renal carcinoma (RCCP1; 605074), Schmidt et al. (1997) found a heterozygous germline 3640T-C transition in exon 17 of the MET gene that resulted in a met1149-to-thr (M1149T) amino acid substitution.


.0002   RENAL CELL CARCINOMA, PAPILLARY, 1

MET, VAL1206LEU
SNP: rs121913669, gnomAD: rs121913669, ClinVar: RCV000014896

In affected members of 2 families with hereditary papillary renal carcinoma (605074), Schmidt et al. (1997) found a heterozygous germline 3810G-T transversion in exon 18 of the MET gene that resulted in a val1206-to-leu (V1206L) amino acid substitution.


.0003   RENAL CELL CARCINOMA, PAPILLARY, 1

MET, VAL1238ILE
SNP: rs121913670, ClinVar: RCV000014897, RCV000221989, RCV001376555, RCV001579843

In affected members of 2 families with hereditary papillary renal carcinoma (605074), Schmidt et al. (1997) found a heterozygous germline 3906G-A transition in exon 19 of the MET gene that resulted in a val1238-to-ile (V1238I) amino acid substitution.


.0004   RENAL CELL CARCINOMA, PAPILLARY, 1

MET, ASP1246ASN
SNP: rs121913671, ClinVar: RCV000014898, RCV000420939

In affected members of 2 families with hereditary papillary renal carcinoma (605074), Schmidt et al. (1997) found a heterozygous germline 3930G-A transition in exon 19 of the MET gene that resulted in an asp1246-to-asn (D1246N) amino acid substitution.


.0005   RENAL CELL CARCINOMA, PAPILLARY, 1

MET, TYR1248CYS
SNP: rs121913246, gnomAD: rs121913246, ClinVar: RCV000014899, RCV000420374, RCV000430628, RCV000441479, RCV001851861, RCV002362584

In affected members of 2 families with hereditary papillary renal carcinoma (605074), Schmidt et al. (1997) found a heterozygous germline 3937G-A transition in exon 19 of the MET gene that resulted in a tyr1248-to-cys (Y1248C) amino acid substitution.


.0006   RENAL CELL CARCINOMA, PAPILLARY, 1, SOMATIC

MET, LEU1213VAL
SNP: rs121913673, ClinVar: RCV000014900

In a sporadic papillary renal carcinoma (605074), Schmidt et al. (1997) identified a 3831C-G transversion in exon 18 of the MET gene, resulting in a leu1213-to-val (L1213V) amino acid substitution.


.0007   RENAL CELL CARCINOMA, PAPILLARY, 1

MET, HIS1112ARG
SNP: rs121913243, gnomAD: rs121913243, ClinVar: RCV000014901, RCV000079490, RCV000433739, RCV001376564, RCV002321481, RCV003407332

In affected members of 2 families and in an unrelated individual, all with papillary renal carcinoma (605074), Schmidt et al. (1998) detected a germline heterozygous A-to-G transition at nucleotide 3529 in exon 16 of the MET gene. The mutation resulted in a his1112-to-arg (H1112R) substitution in the tyrosine kinase domain of the protein. Haplotype analysis suggested that a founder effect was responsible for the disorder in the 2 families.

In tumors from 2 patients from the 2 families described by Schmidt et al. (1998), Zhuang et al. (1998) showed duplication of the mutant MET allele. One patient was asymptomatic but had been examined by CT scan at age 44 because of family history of renal cancer. Multiple tumor nodules were found in both kidneys. The second patient was a member of the second family with 13 affected members, 4 of whom were asymptomatic and identified as having renal tumors by CT scan. This patient had multiple, bilateral papillary renal tumors and had undergone unilateral nephrectomy.


.0008   HEPATOCELLULAR CARCINOMA, CHILDHOOD TYPE, SOMATIC

MET, THR1191ILE
SNP: rs121913675, ClinVar: RCV000014902

In a study of 75 primary liver cancers, Park et al. (1999) identified 3 missense mutations within the tyrosine kinase domain of the MET gene in 10 childhood hepatocellular carcinomas (HCC; 114550), while no mutations were detected in 16 adult HCCs, 21 cholangiocarcinomas, or 28 hepatoblastomas. The sequencing analysis of the MET gene was limited to the tyrosine kinase domain (exons 15 to 19). One mutation was a change of codon 1191 in exon 17 from ACT (thr) to ATT (ile). A second mutation was a change of codon 1268 in exon 19 from ATG (met) to ATA (ile) (164860.0009). The third mutation was a change of codon 1262 in exon 19 from AAG (lys) to AGG (arg) (164860.0010). The very short incubation period from hepatitis B virus infection to the genesis of childhood HCC as compared with adult HCC suggests that there may be an additional mechanism that accelerates the carcinogenesis of childhood HCC. Park et al. (1999) suggested that mutations of the tyrosine kinase domain of the MET gene may play such a role in the acceleration of the carcinogenesis in childhood HCC.


.0009   HEPATOCELLULAR CARCINOMA, CHILDHOOD TYPE, SOMATIC

MET, MET1268ILE
SNP: rs121913676, ClinVar: RCV000014903, RCV000427546

See 164860.0008 and Park et al. (1999).


.0010   HEPATOCELLULAR CARCINOMA, CHILDHOOD TYPE, SOMATIC

MET, LYS1262ARG
SNP: rs121913677, ClinVar: RCV000014904

See 164860.0008 and Park et al. (1999).


.0011   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

MET, -20G-C ({dbSNP rs1858830})
SNP: rs1858830, gnomAD: rs1858830, ClinVar: RCV000014905

This variant, formerly titled AUTISM, ASSOCIATION WITH, 9, has been reclassified as a variant of unknown significance because its contribution to autism (see 611015) has not been confirmed.

Campbell et al. (2006) identified a G-C transversion (rs1858830) in the promoter of the MET gene, located 20 basepairs 5-prime to the transcriptional start site. In vitro functional expression studies showed that the C allele resulted in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. In 204 families with autism, Campbell et al. (2006) found a significant association between autism and the -20C allele. The association was confirmed in a replication study of 539 additional autistic families and in the combined sample. Multiplex families, in which more than 1 child has autism, exhibited the strongest allelic association (p = 0.000007). In case-control analysis, the relative risk for autism was 2.27 for the CC genotype and 1.67 for the GC genotype compared to the GG genotype. No functional studies were performed.


.0012   DEAFNESS, AUTOSOMAL RECESSIVE 97 (1 family)

MET, PHE841VAL
SNP: rs794728016, ClinVar: RCV000185580, RCV000202585

In 9 affected members of a large consanguineous Pakistani family (HLGM17) segregating autosomal recessive nonsyndromic deafness (DFNB97; 616705), Mujtaba et al. (2015) identified homozygosity for a c.2521T-G transversion (c.2521T-G, NM_000245.2) in exon 11 of the MET gene, resulting in a phe841-to-val (F841V) substitution at a highly conserved residue within the IPT4 domain. The mutation segregated fully with disease in the family and was not found in 400 Pakistani controls or in the Exome Variant Server, ExAC, or 1000 Genomes Project databases. The authors noted that because only exonic regions were analyzed, it was possible that F841V represents a variant in linkage disequilibrium with the true pathogenic allele.


.0013   OSTEOFIBROUS DYSPLASIA, SUSCEPTIBILITY TO

MET, 26-BP DEL, NT3010
SNP: rs869320706, ClinVar: RCV000210883

In 8 affected individuals from a 4-generation family with osteofibrous dysplasia (OSFD; 607278), originally reported by Beals and Fraser (1976), Gray et al. (2015) identified heterozygosity for a 26-bp deletion in the MET gene (c.3010_3028+8del, NM_000245.2) (Leu964_Asp1010del) that includes the donor splice site at the exon 14/intron 14 junction. The deletion was also present in 1 unaffected family member, but was not found in the Exome Variant Server or dbSNP build 131 databases. RT-PCR of cultured patient dermal fibroblasts showed that the deletion results in exclusion of exon 14 from the mature MET transcript, predicting the in-frame omission of the phylogenetically conserved juxtamembrane domain of the MET receptor. In transfected HEK293 cells, Gray et al. (2015) demonstrated that MET mutants involving deletion of exon 14 stabilize the MET receptor, resulting in a gain of function.


.0014   OSTEOFIBROUS DYSPLASIA, SUSCEPTIBILITY TO

MET, IVS14, G-T, +1
SNP: rs869320707, ClinVar: RCV000210870, RCV001254319

In a family with osteofibrous dysplasia (OSFD; 607278) that was previously studied by Karol et al. (2005), Gray et al. (2015) identified a heterozygous splice site mutation in intron 14 of the MET gene (c.3028+1G-T, NM_000245.2) (Leu964_Asp1010del) that was present in 5 affected and 4 unaffected family members. The same splice site mutation was detected in an affected mother and son from a second family, as well as in normal tissue adjacent to an excised lesion from an unrelated female patient with OSFD, who was originally reported by Sunkara et al. (1997). RT-PCR on lymphoblastoid cell lines from the first family and excised lesional bone tissue from the second family showed that the splice site mutation results in exclusion of exon 14 from mature MET transcript, predicting the in-frame omission of the phylogenetically conserved juxtamembrane domain of the MET receptor. In transfected HEK293 cells, Gray et al. (2015) demonstrated that MET mutants involving deletion of exon 14 stabilize the MET receptor, resulting in a gain of function.


.0015   ARTHROGRYPOSIS, DISTAL, TYPE 11 (1 family)

MET, TYR1234CYS
SNP: rs1554400286, ClinVar: RCV000626485, RCV002279723

In 11 members of a Chinese family with distal arthrogryposis type 11 (DA11; 620019), Zhou et al. (2019) identified heterozygosity for a c.3701A-G transition (c.3701A-G, NM_000245.2) in the MET gene, resulting in a tyr1234-to-cys (Y1234C) substitution. The mutation was identified by whole-exome sequencing and segregated with the disorder in the family. Transfection studies in HEK293T cells showed that the mutant MET protein was unable to be phosphorylated after treatment with human hepatocyte growth factor.


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Contributors:
Hilary J. Vernon - updated : 08/25/2022
Marla J. F. O'Neill - updated : 04/12/2016
Marla J. F. O'Neill - updated : 12/18/2015
Ada Hamosh - updated : 10/15/2015
Ada Hamosh - updated : 7/15/2014
Paul J. Converse - updated : 10/20/2011
Ada Hamosh - updated : 3/26/2008
Ada Hamosh - updated : 6/14/2007
Cassandra L. Kniffin - updated : 1/4/2007
Paul J. Converse - updated : 10/18/2005
Marla J. F. O'Neill - updated : 3/23/2005
Ada Hamosh - updated : 10/29/2003
Patricia A. Hartz - updated : 10/28/2002
Dawn Watkins-Chow - updated : 6/12/2002
Stylianos E. Antonarakis - updated : 7/3/2001
Victor A. McKusick - updated : 3/21/2000
Victor A. McKusick - updated : 3/24/1999
Victor A. McKusick - updated : 12/10/1998
Victor A. McKusick - updated : 8/28/1998
Victor A. McKusick - updated : 1/13/1998
Victor A. McKusick - updated : 11/6/1997
Victor A. McKusick - updated : 4/30/1997
Moyra Smith - updated : 12/13/1996

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
carol : 08/25/2022
carol : 01/23/2020
carol : 08/23/2016
alopez : 04/12/2016
carol : 12/18/2015
alopez : 10/15/2015
carol : 2/16/2015
alopez : 7/15/2014
carol : 11/14/2013
mgross : 10/7/2013
mgross : 10/20/2011
mgross : 10/20/2011
carol : 9/15/2011
ckniffin : 9/13/2011
alopez : 4/5/2010
ckniffin : 11/17/2009
alopez : 3/27/2008
alopez : 3/27/2008
terry : 3/26/2008
alopez : 6/28/2007
terry : 6/14/2007
ckniffin : 5/16/2007
carol : 5/14/2007
ckniffin : 5/10/2007
ckniffin : 3/12/2007
wwang : 1/25/2007
ckniffin : 1/4/2007
mgross : 10/18/2005
alopez : 3/23/2005
alopez : 3/23/2005
alopez : 11/7/2003
alopez : 10/29/2003
terry : 10/29/2003
mgross : 10/28/2002
mgross : 10/28/2002
cwells : 6/12/2002
mgross : 7/3/2001
carol : 7/20/2000
terry : 3/21/2000
carol : 9/20/1999
mgross : 4/2/1999
mgross : 3/30/1999
terry : 3/24/1999
carol : 12/15/1998
carol : 12/15/1998
terry : 12/10/1998
alopez : 8/31/1998
terry : 8/28/1998
carol : 3/28/1998
alopez : 1/13/1998
dholmes : 12/24/1997
jenny : 11/12/1997
terry : 11/6/1997
alopez : 8/8/1997
alopez : 5/13/1997
mark : 4/30/1997
terry : 4/30/1997
jenny : 12/23/1996
mark : 12/13/1996
jenny : 12/12/1996
mark : 12/9/1996
mark : 6/9/1996
carol : 1/6/1993
supermim : 3/16/1992
carol : 3/4/1991
carol : 2/28/1991
supermim : 3/20/1990
supermim : 1/13/1990