C-Met

Met proto-oncogene (hepatocyte growth factor receptor)
PDB rendering based on 1r0p.
Identifiers
Symbol(s)	MET; HGFR; RCCP2
External IDs	OMIM: 164860 MGI: 96969 Homologene: 206
Gene ontology Molecular Function: • nucleotide binding • protein-tyrosine kinase activity • receptor activity • hepatocyte growth factor receptor activity • protein binding • ATP binding • transferase activity Cellular Component: • membrane fraction • integral to plasma membrane • basal plasma membrane • membrane Biological Process: • activation of MAPK activity • cell surface receptor linked signal transduction • multicellular organismal development • brain development • muscle development • adult behavior • protein amino acid autophosphorylation • hepatocyte growth factor receptor signaling pathway • myoblast proliferation
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	4233	17295
Ensembl	ENSG00000105976	ENSMUSG00000009376
Uniprot	P08581	A1A597
Refseq	NM_000245 (mRNA) NP_000236 (protein)	NM_008591 (mRNA) NP_032617 (protein)
Location	Chr 7: 116.1 - 116.22 Mb	Chr 6: 17.44 - 17.52 Mb
Pubmed search	[1]	[2]

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[3] 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 [4]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[5], 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.
• 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.
• 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.
• 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.

External links

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