MET (Hepatocyte Growth Factor Receptor)
MET, Hepatocyte Growth Factor receptor, Scatter Factor receptor refer to a single-pass class I trans-membrane tyrosine kinase (TrK) receptor typically, but not exclusively, associated with adult epithelial cells. While MET is not generally expressed on adult mesenchymal cells, it is constitutively expressed on mesenchymal stem cells. The Met (mesenchymal-epithelial transition factor) proto-oncogene (gene map locus 7q31) codes for a 1,390 amino-acid single-chain polypeptide (alternatively spliced isoform plus 18 amino acids) which after removal of a 24 amino acid signal peptide is proteolysed into alpha- (50kDa) and beta- (145kDa) subunits which are disulfide bridge linked to form a heterodimer.
The alpha-subunit is entirely extracellular, whereas the beta-subunit extends across the membrane and has a cytoplasmic C-terminal. The alpha-subunit along with an N-terminal segment of the beta-chain forms a Sema domain, homologous to semaphorins. The beta-chain N-terminal also contains three immunoglobulin-like, IPT/TIG domains believed to mediate cell scattering processes such as dissociation, motility and invasion of extra-cellular matrices. The alpha and beta chains are N-glycosylated (GlcNac) at multiple sites. The beta-chain contains threonine (977); serine (985, 988, and 990) and tyrosine (1003, 1234, 1235 and 1356) phosphorylation sites. Tyr1234 and Tyr1235 are trans-phosphorylated during MET activation. Phosphorylation of Ser985 inhibits receptor kinase activity. Phosphorylation of Tyr1349 and Tyr1359 allows recruitment of downstream SH2 domain containing adaptor proteins.
MET initiates cell-signaling within numerous pathways including: the RAS-RAF-MAPK-ERK cascade; the CRK-MAP4K-JNK cascade; signal transducer and activator of transcription (STAT-3); the PI3K-AKT pathway; the beta catenin, Wnt signaling pathway; and the CRKL-DOCK 180 pathway leading to Rho, Rac1 and CDC42 activation.
MET is expressed primarily in stem and progenitor cells that need to grow invasively to regenerate tissue in the embryo or damaged adult tissue. MET activation of these pathways results in a complex response referred to as invasive growth involving processes such as mitogenesis, motogenesis, morphogenesis and the ability to survive anoikis, apoptosis induced by loss of normal cell matrix associations. MET is essential for a variety of regenerative; angiogenesis, liver regeneration, wound healing, bone remodeling and embryogenic; gastrulation and angiogenesis processes.
MET is involved in a number of diseases including Autism; Malaria and Listeria bacterial infections; and cancer. The processes activated by MET for normal regeneration and embryonic development can become dysregulated leading to cancers which are invasive and prone to metastasize. Cancer associated with MET dysregulation include gastric cancer, papillary renal carcinoma (HPRC, RCCP2), and hepatocellular carcinoma (HCC). Some cancer stem cells responsible for invasive cancer growth express MET.
Sigma offers antibodies, shRNAs and other products useful for the study of the MET Gene.
References:
Gentile A, et al. (2008) The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev. 27: 85-94.
Conway K, et al. (2007) Hepatocyte growth factor regulation: an integral part of why wounds become chronic. Wound Repair Regen. 15: 683-692.
Corso S, et al. (2005) Cancer therapy: can the challenge be MET? Trends Mol Med. 11: 284-292.
Forte G, et al. (2006) Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation. Stem Cells. 24: 23-33.
Neuss S, et al. (2004) Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells. 22: 405-414.
Parr C and Jiang WG. (2001) Expression of hepatocyte growth factor/scatter factor, its activator, inhibitors and the c-Met receptor in human cancer cells. Int J Oncol. 19: 857-863.
Footnote: Gene Data Sources: HGNC, Entrez Gene, UniProt/Swiss-Prot, UniProt/TrEMBL, GDB, OMIM, GeneLoc, Ensembl.
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