C-Met

Met proto-oncogene (hepatocyte growth factor receptor)
PDB rendering based on 1r0p.
Identifiers
Symbols	MET ; HGFR; RCCP2
External IDs	Template:OMIM5 Template:MGI HomoloGene: 206
Gene ontology Molecular function Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Cellular component Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Biological process Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO
RNA expression pattern
More reference expression data
Orthologs
Template:GNF Ortholog box
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a

Overview

c-Met (Mesenchymal epithelial transition factor) is a proto-oncogene that encodes for a tyrosine kinase membrane receptor for hepatocyte growth factor/scatter factor (HGF/SF). The proto-oncogene MET product is the hepatocyte growth factor receptor and encodes tyrosine-kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor. Various mutations in the MET gene are associated with papillary renal carcinoma.

Fields of HGF/c-Met involvement

The c-Met protein is expressed mostly in epithelial cells, but also[1] in endothelial cells, neural cells, hepatocytes, hematopoietic cells, melanocytes. c-Met might well be one of the most important membrane receptors. Its activation plays a key role in cellular physiology : mitogenesis, motogenesis, morphogenesis. HGF/SF seems essentially produced by cells of mesenchymal origin.

HGF/c-Met and Cancer

When HGF/SF activates c-Met, the first proteins to be activated [2]downstream are Grb2 (growth factor receptor bound protein 2) and Gab 1 (growth factor receptor bound protein 2 associated binder 1). Grb2 in turn may activate a number of kinase pathways, including the pathway from Ras to Raf to Mek and to MAPK(mitogen-activated protein kinase). Gab 1 activates PI3K (phosphoinositide 3 kinase), which activates STAT3 (signal transducer and activator of transcription). c-Met activation also induces activation of beta catenin, a key component of the wnt pathway[3], which translocates into the nucleus and participates in transcription regulation.

The HGF/c-Met pathway plays an important role in the development of cancer. First through the activation of key oncogenic pathways (Ras, PI3K/STAT3, beta catenin), secondly through endothelial cell proliferation (neoangiogenesis), thirdly through increased protease production and hence cell dissociation leading to metastasis.

Cancer therapies targeting HGF/c-Met

Many new therapies,some of them in phase I or II clinical trials are aimed at the HGF/c-Met pathway :

- anti HGF monoclonal antibodies : a humanized one from AVEO (AV299), a fully human one from AMGEN (AMG102)

- truncated variants of c-Met that act as decoys : CGEN241 from COMPUGEN

- protein kinase inhibitors that block c-Met induced pathways : ARQ197 from ARQULE, XL880 from EXELIXIS, SGX523 from SGX Pharmaceuticals, MP470 from SUPERGEN, PF2341066 from PFIZER

See also

• Tpr-met fusion protein

Further reading

• Peruzzi B, Bottaro DP (2006). "Targeting the c-Met signaling pathway in cancer". Clin. Cancer Res. 12 (12): 3657–60. doi:10.1158/1078-0432.CCR-06-0818. PMID 16778093.
• Birchmeier, C., Birchmeier, W., Gheradi, E., & Vande Woude, G. F. (2003). Met, metastasis, motility and more. Nature Reviews Molecular Cell Biology, 4, 915—925. PMID 14685170 doi:10.1038/nrm1261
• Zhang, Y., & Vande Woude, G. F. (2003). HGF/SF-Met signaling in the control of branching morphogenesis and invasion. Journal of Cellular Biochemistry, 88, 408—417. PMID 12520544 doi:10.1002/jcb.10358
• Paumelle, R., Tulashe, D., Kherrouche, Z., Plaza, S., Leroy, C., Reveneau, S., Vandenbunder, B., & Fafeur, V. (2002). Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene, 21, 2309—2319. PMID 11948414 doi:10.1038/sj.onc.1205297
• Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". EXS. 65: 131–65. PMID 8380735.
• Maulik G, Shrikhande A, Kijima T; et al. (2002). "Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition". Cytokine Growth Factor Rev. 13 (1): 41–59. PMID 11750879.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Ma PC, Maulik G, Christensen J, Salgia R (2004). "c-Met: structure, functions and potential for therapeutic inhibition". Cancer Metastasis Rev. 22 (4): 309–25. PMID 12884908.CS1 maint: Multiple names: authors list (link)
• Knudsen BS, Edlund M (2004). "Prostate cancer and the met hepatocyte growth factor receptor". Adv. Cancer Res. 91: 31–67. doi:10.1016/S0065-230X(04)91002-0. PMID 15327888.
• Dharmawardana PG, Giubellino A, Bottaro DP (2005). "Hereditary papillary renal carcinoma type I.". Curr. Mol. Med. 4 (8): 855–68. PMID 15579033.CS1 maint: Multiple names: authors list (link)
• Kemp LE, Mulloy B, Gherardi E (2006). "Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors". Biochem. Soc. Trans. 34 (Pt 3): 414–7. doi:10.1042/BST0340414. PMID 16709175.CS1 maint: Multiple names: authors list (link)

External links

• Proto-Oncogene+Proteins+c-met at the US National Library of Medicine Medical Subject Headings (MeSH)
• UniProtKB/Swiss-Prot entry P08581: MET_HUMAN, ExPASy (Expert Protein Analysis System) proteomics server of the Swiss Institute of Bioinformatics (SIB).