MET Receptor Activation

Stable Identifier
Homo sapiens
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Hepatocyte growth factor (HGF), the ligand for MET receptor tyrosine kinase (RTK), is secreted into the extracellular matrix (ECM) as an inactive single chain precursor (pro-HGF). The biologically active HGF is the heterodimer of alpha and beta chains that are produced via proteolytic cleavage of pro-HGF by the plasma membrane bound serine protease Hepsin (HPN) (Kirchhofer et al. 2005, Owen et al. 2010) or the ECM-associated serine protease Hepatocyte growth factor activator (HGFAC, commonly known as HGFA) (Shia et al. 2005). HGF binds to the extracellular SEMA and PSI domains of MET RTK, inducing a conformational change that enables MET dimerization or oligomerization (Kirchhofer et al. 2004, Stamos et al. 2004, Hays and Watowich 2004, Gherardi et al. 2006). MET dimers trans-autophosphorylate on tyrosine residues in the activation loop, leading to increased kinase activity, and on tyrosine residues at the cytoplasmic tail that serve as docking sites for adapter proteins involved in MET signal transduction (Ferracini et al. 1991, Longati et al. 1994, Rodrigues and Park 1994, Ponzetto et al. 1994).
CD44v6 was implicated as a MET co-receptor, but its role has been disputed (Orian-Rousseau et al. 2002, Dortet et al. 2010, Olaku et al. 2011, Hasenauer et al. 2013, Elliot et al. 2014).

Literature References
PubMed ID Title Journal Year
15713485 Conformational lability in serine protease active sites: structures of hepatocyte growth factor activator (HGFA) alone and with the inhibitory domain from HGFA inhibitor-1B

Kirchhofer, D, Shia, S, Corpuz, RT, Stamos, J, Santell, L, Fan, B, Eigenbrot, C, Wu, J, Lazarus, RA

J. Mol. Biol. 2005
15792801 Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2

Kirchhofer, D, Lipari, MT, Fan, B, Peek, M, Billeci, K, Moran, P

FEBS Lett. 2005
16537482 Structural basis of hepatocyte growth factor/scatter factor and MET signalling

Ofverstedt, LG, Sandin, S, Svergun, DI, Finch, J, Miguel, RN, Petoukhov, MV, Vande Woude, GF, Gherardi, E, Skoglund, U, Youles, ME, Blundell, TL

Proc. Natl. Acad. Sci. U.S.A. 2006
24823486 Activation of c-Met and upregulation of CD44 expression are associated with the metastatic phenotype in the colorectal cancer liver metastasis model

Elliott, VA, Zaytseva, YY, Evers, BM, Rychahou, P

PLoS ONE 2014
23626807 Internalization of Met requires the co-receptor CD44v6 and its link to ERM proteins

Malinger, D, Orian-Rousseau, V, Hasenauer, S, Pace, G, von Au, A, Koschut, D, Matzke, A

PLoS ONE 2013
15301554 Oligomerization-dependent changes in the thermodynamic properties of the TPR-MET receptor tyrosine kinase

Watowich, SJ, Hays, JL

Biochemistry 2004
7513258 A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family

Bardelli, A, Comoglio, PM, Zhen, Z, Ponzetto, C, Giordano, S, dalla Zonca, P, Maina, F, Panayotou, G, Graziani, A

Cell 1994
1655790 Identification of the major autophosphorylation site of the Met/hepatocyte growth factor receptor tyrosine kinase

Naldini, L, Comoglio, PM, Ferracini, R, Longati, P, Vigna, E

J. Biol. Chem. 1991
20015050 Pericellular activation of hepatocyte growth factor by the transmembrane serine proteases matriptase and hepsin, but not by the membrane-associated protease uPA

Li, J, Qiu, D, Ellis, V, Alves, J, Schumacher, AM, Owen, KA, Kilpatrick, LM, Harris, JL

Biochem. J. 2010
21680714 c-Met recruits ICAM-1 as a coreceptor to compensate for the loss of CD44 in Cd44 null mice

Mitchell, C, Orian-Rousseau, V, Sakkaravarthi, A, Hasenauer, S, Pace, G, Olaku, V, Ponta, H, Matzke, A

Mol. Biol. Cell 2011
8208547 Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase

Rodrigues, GA, Park, M

Oncogene 1994
8302603 Tyrosines1234-1235 are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor)

Naldini, L, Bardelli, A, Comoglio, PM, Ponzetto, C, Longati, P

Oncogene 1994
12464636 CD44 is required for two consecutive steps in HGF/c-Met signaling

Orian-Rousseau, V, Herrlich, P, Chen, L, Sleeman, JP, Ponta, H

Genes Dev. 2002
15167892 Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor

Kirchhofer, D, Wiesmann, C, Stamos, J, Yao, X, Lazarus, RA

EMBO J. 2004
20670691 CD44-independent activation of the Met signaling pathway by HGF and InlB

Bonazzi, M, Veiga, E, Cossart, P, Dortet, L

Microbes Infect. 2010
15218027 Structural and functional basis of the serine protease-like hepatocyte growth factor beta-chain in Met binding and signaling

Kirchhofer, D, Billeci, KL, Lipari, MT, Wiesmann, C, Yao, X, Santell, L, Maun, HR, Eigenbrot, C, Peek, M, Lazarus, RA, Moran, P

J. Biol. Chem. 2004
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