Signaling by MET

Stable Identifier
Homo sapiens
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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
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