Reactome | Signaling by MET

Signaling by MET

Stable Identifier

R-HSA-6806834

DOI

10.3180/R-HSA-6806834.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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MET is a receptor tyrosine kinase (RTK) (Cooper et al. 1984, Park et al. 1984) activated by binding to its ligand, Hepatocyte growth factor/Scatter factor (HGF/SF) (Bottaro et al. 1991, Naldini et al. 1991). Similar to other related RTKs, such as EGFR, ligand binding induces MET dimerization and trans-autophosphorylation, resulting in the active MET receptor complex (Ferracini et al. 1991, Longati et al. 1994, Rodrigues and Park 1994, Kirchhofer et al. 2004, Stamos et al. 2004, Hays and Watowich 2004). Phosphorylated tyrosines in the cytoplasmic tail of MET serve as docking sites for binding of adapter proteins, such as GRB2, SHC1 and GAB1, which trigger signal transduction cascades that activate PI3K/AKT, RAS, STAT3, PTK2, RAC1 and RAP1 signaling (Ponzetto et al. 1994, Pelicci et al. 1995, Weidner et al. 1995, Besser et al. 1997, Shen and Novak 1997, Beviglia and Kramer 1999, Rodrigues et al. 2000, Sakkab et al. 2000, Schaeper et al. 2000, Lamorte et al. 2002, Wang et al. 2002, Chen and Chen 2006, Palamidessi et al. 2008, Chen et al. 2011, Murray et al. 2014).
Activation of PLC gamma 1 (PLCG1) signaling by MET remains unclear. It has been reported that PLCG1 can bind to MET directly (Ponzetto et al. 1994) or be recruited by phosphorylated GAB1 (Gual et al. 2000). Tyrosine residue Y307 of GAB1 that serves as docking sites for PLCG1 may be phosphorylated either by activated MET (Watanabe et al. 2006) or SRC (Chan et al. 2010). Another PCLG1 docking site on GAB1, tyrosine residue Y373, was reported as the SRC target, while the kinase for the main PLCG1 docking site, Y407 of GAB1, is not known (Chan et al. 2010).
Signaling by MET promotes cell growth, cell survival and motility, which are essential for embryonic development (Weidner et al. 1993, Schmidt et al. 1995, Uehara et al. 1995, Bladt et al. 1995, Maina et al. 1997, Maina et al. 2001, Helmbacher et al. 2003) and tissue regeneration (Huh et al. 2004, Borowiak et al. 2004, Liu 2004, Chmielowiec et al. 2007). MET signaling is frequently aberrantly activated in cancer, through MET overexpression or activating MET mutations (Schmidt et al. 1997, Pennacchietti et al. 2003, Smolen et al. 2006, Bertotti et al. 2009).
Considerable progress has recently been made in the development of HGF-MET inhibitors in cancer therapy. These include inhibitors of HGF activators, HGF inhibitors and MET antagonists, which are protein therapeutics that act outside the cell. Kinase inhibitors function inside the cell and have constituted the largest effort towards MET-based therapeutics (Gherardi et al. 2012).
Pathogenic bacteria of the species Listeria monocytogenes, exploit MET receptor as an entryway to host cells (Shen et al. 2000, Veiga and Cossart 2005, Neimann et al. 2007).
For review of MET signaling, please refer to Birchmeier et al. 2003, Trusolino et al. 2010, Gherardi et al. 2012, Petrini 2015.

Literature References

PubMed ID	Title	Journal	Year
14685170	Met, metastasis, motility and more Vande Woude, GF, Gherardi, E, Birchmeier, W, Birchmeier, C	Nat. Rev. Mol. Cell Biol.	2003
19996456	Only a subset of Met-activated pathways are required to sustain oncogene addiction Gastaldi, S, Bertotti, A, Comoglio, PM, Rolland-Valognes, G, Hickman, JA, Torti, D, Medico, E, Burbridge, MF, Giordano, S, Trusolino, L, Corso, S, Lockhart, BP, Galimi, F	Sci Signal	2009
1846706	Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product Chan, AM, Kmiecik, TE, Aaronson, SA, Rubin, JS, Vande Woude, GF, Faletto, DL, Bottaro, DP	Science	1991
22270953	Targeting MET in cancer: rationale and progress Vande Woude, G, Gherardi, E, Birchmeier, W, Birchmeier, C	Nat. Rev. Cancer	2012
6590967	Molecular cloning of a new transforming gene from a chemically transformed human cell line Huebner, K, Croce, CM, Park, M, Blair, DG, Vande Woude, GF, Cooper, CS, Tainsky, MA	Nature	1984
16461907	Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752 Mohapatra, G, Okimoto, RA, Haber, DA, Muir, B, Bell, DW, Kim, WJ, Sgroi, DC, Settleman, J, Smolen, GA, Archibald, H, Christensen, JG, Sordella, R, Barmettler, A	Proc. Natl. Acad. Sci. U.S.A.	2006
9070211	DDT stimulates c-erbB2, c-met, and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation, and proliferation of human breast epithelial cells Shen, K, Novak, RF	Biochem. Biophys. Res. Commun.	1997
9140397	Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas Schmidt, L, Bernues, M, Slife, L, Chen, F, Stackhouse, T, Brauch, H, Dean, M, Zbar, B, Casadevall, C, Linehan, WM, Allikmets, R, Orcutt, ML, Zamarron, A, Zhuang, Z, Kishida, T, Richard, S, Niehans, G, Lipan, J, Chidambaram, A, Geil, L, Feltis, JT, Choyke, P, Bergerheim, UR, Duh, FM, Storkel, S, Tsui, LC, Lubensky, I, Lerman, MI, Scherer, SW, Lips, CJ, Glenn, G, Walther, MM, Moch, H, Hughson, MD, Decker, J	Nat. Genet.	1997
18614017	Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration Faretta, M, Di Fiore, PP, Palamidessi, A, Scita, G, Garré, M, Testa, I, Diaspro, A, Mione, M, Frittoli, E, Lanzetti, L	Cell	2008
15180923	Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action Liu, Y	Am. J. Physiol. Renal Physiol.	2004
9038378	Regulation of the urokinase-type plasminogen activator gene by the oncogene Tpr-Met involves GRB2 Bardelli, A, Comoglio, PM, Besser, D, Thelen, M, Nagamine, Y, Ponzetto, C, Didichenko, S	Oncogene	1997
7708691	Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells Riethmacher, D, Birchmeier, W, Weidner, KM, Sachs, M	Proc. Natl. Acad. Sci. U.S.A.	1995
2423252	Mechanism of met oncogene activation Park, M, Blair, DG, Vande Woude, GF, O'Brien, SJ, Dean, M, Cooper, CS, Schmidt, M	Cell	1986
12726861	Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene Mazzone, M, Giordano, S, Galluzzo, M, Comoglio, PM, Pennacchietti, S, Michieli, P	Cancer Cell	2003
19881549	Differential phosphorylation of the docking protein Gab1 by c-Src and the hepatocyte growth factor receptor regulates different aspects of cell functions Chan, PC, Chen, HC, Lai, CC, Sudhakar, JN	Oncogene	2010
8384622	The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells Birchmeier, W, Weidner, KM, Sachs, M	J. Cell Biol.	1993
1827664	Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET Naldini, L, Comoglio, PM, Zarnegar, R, Gaudino, G, Michalopoulos, GK, Vigna, E, Narsimhan, RP	Oncogene	1991
25992381	Biology of MET: a double life between normal tissue repair and tumor progression Petrini, I	Ann Transl Med	2015
10753869	Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL Lewitzky, M, Sakkab, D, Posern, G, Feller, SM, Birchmeier, W, Sachs, M, Schaeper, U	J. Biol. Chem.	2000
12147692	Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM Wang, D, Li, Z, Messing, EM, Wu, G	J. Biol. Chem.	2002
10734310	Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis Williams, TA, Gual, P, Giordano, S, Rocchi, S, Comoglio, PM, Van Obberghen, E	Oncogene	2000
12006644	Crk adapter proteins promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions Lamorte, L, Naujokas, M, Park, M, Royal, I	Mol. Biol. Cell	2002
16782899	Direct interaction of focal adhesion kinase (FAK) with Met is required for FAK to promote hepatocyte growth factor-induced cell invasion Chen, HC, Chen, SY	Mol. Cell. Biol.	2006
20802513	Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition Chen, CL, Chan, PC, Chen, HC, Chen, TH	Oncogene	2011
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
7731718	The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein Bardelli, A, Zhen, Z, Waterfield, MD, Lanfrancone, L, Salcini, AE, Ponzetto, C, Giordano, S, Pelicci, G, Pelicci, PG, Panayotou, G	Oncogene	1995
8208547	Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase Rodrigues, GA, Park, M	Oncogene	1994
10521801	HGF induces FAK activation and integrin-mediated adhesion in MTLn3 breast carcinoma cells Kramer, RH, Beviglia, L	Int. J. Cancer	1999
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
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
17403932	c-Met is essential for wound healing in the skin Wehland, J, Morkel, M, Munz, B, Chmielowiec, J, Werner, S, Stradal, T, Birchmeier, W, Birchmeier, C, Borowiak, M	J. Cell Biol.	2007
24518591	Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation van Aelst, L, Didier, S, Byrne, AT, Murray, DW, Paulino, V, Ruggieri, R, Tran, NL, Chan, A, Symons, M	Br. J. Cancer	2014
10648629	A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling Falasca, M, Rodrigues, GA, Schlessinger, J, Ong, SH, Zhang, Z	Mol Cell Biol	2000
15070743	Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair Sánchez, A, Huh, CG, Factor, VM, Thorgeirsson, SS, Uchida, K, Conner, EA	Proc. Natl. Acad. Sci. U.S.A.	2004
11081636	InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase Park, M, Naujokas, M, Ireton, K, Shen, Y	Cell	2000
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
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
7651534	Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud Birchmeier, C, Riethmacher, D, Bladt, F, Aguzzi, A, Isenmann, S	Nature	1995
17662939	Structure of the human receptor tyrosine kinase met in complex with the Listeria invasion protein InlB Heinz, DW, Ferraris, D, Schmidt, S, Gherardi, E, van den Heuvel, J, Jäger, V, Butler, PJ, Niemann, HH	Cell	2007
10871282	Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses Kempkes, B, Fuchs, KP, Birchmeier, W, Sachs, M, Gehring, NH, Schaeper, U	J. Cell Biol.	2000
7854453	Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor Mori, C, Kitamura, N, Noda, T, Kuno, J, Minowa, O, Uehara, Y, Shiota, K	Nature	1995
11430831	Coupling Met to specific pathways results in distinct developmental outcomes Andres, R, Porthin, A, Panté, G, Klein, R, Ponzetto, C, Davies, AM, Helmbacher, F, Maina, F	Mol. Cell	2001
7854452	Scatter factor/hepatocyte growth factor is essential for liver development Brinkmann, V, Zschiesche, W, Sharpe, M, Birchmeier, C, Gherardi, E, Bladt, F, Schmidt, C, Goedecke, S	Nature	1995
15301554	Oligomerization-dependent changes in the thermodynamic properties of the TPR-MET receptor tyrosine kinase Watowich, SJ, Hays, JL	Biochemistry	2004
21102609	MET signalling: principles and functions in development, organ regeneration and cancer Bertotti, A, Comoglio, PM, Trusolino, L	Nat. Rev. Mol. Cell Biol.	2010
15249655	Met provides essential signals for liver regeneration Strehle, M, Trautwein, C, Wüstefeld, T, Garratt, AN, Birchmeier, C, Borowiak, M	Proc. Natl. Acad. Sci. U.S.A.	2004
16113677	Listeria hijacks the clathrin-dependent endocytic machinery to invade mammalian cells Veiga, E, Cossart, P	Nat. Cell Biol.	2005
9407027	Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons Hilton, MC, Klein, R, Ponzetto, C, Davies, AM, Maina, F	Genes Dev.	1997
12948444	Met signaling is required for recruitment of motor neurons to PEA3-positive motor pools Klein, R, Dessaud, E, Henderson, CE, deLapeyriere, O, Arber, S, Helmbacher, F, Maina, F	Neuron	2003