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Gene Review

MET  -  MET proto-oncogene, receptor tyrosine kinase

Homo sapiens

Synonyms: AUTS9, HGF receptor, HGF/SF receptor, HGFR, Hepatocyte growth factor receptor, ...
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Disease relevance of MET


Psychiatry related information on MET


High impact information on MET

  • The same bidentate motif is conserved in the evolutionarily related receptors Sea and Ron, suggesting that in all members of the HGF/SF receptor family, signal transduction is channeled through a multifunctional binding site [6].
  • Inhibition of complex formation is sufficient to block HGF receptor internalization and to enhance HGF-induced signal transduction and biological responses [7].
  • Cbl, in turn, binds and ubiquitinates activated HGF receptor, and by recruiting the endophilin-CIN85 complex, it regulates receptor internalization [7].
  • The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met [7].
  • These data provide further evidence of a relationship between receptor-mediated signalling and endocytosis, and disclose a novel functional role for Cbl in HGF receptor signalling [7].

Chemical compound and disease context of MET


Biological context of MET


Anatomical context of MET

  • Upon ligand binding, hepatocyte growth factor (HGF) receptor (Met) is polyubiquitinated and degraded; however, the mechanisms underlying HGF receptor endocytosis are not yet known [7].
  • Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment [12].
  • We observed that c-Met is predominantly expressed on CD38(+)CD77(+) tonsillar B cells localized in the dark zone of the GC (centroblasts) [12].
  • Here we show that epithelial cells, in which the HGF receptor is naturally expressed, contain FAP68 and not FAP48 proteins [15].
  • In the present study, we explored the expression of CD44-HS, c-Met, and HGF/SF in the normal human colon mucosa, and in colorectal adenomas and carcinomas, as well as their interaction in colorectal cancer cell lines [2].

Associations of MET with chemical compounds


Physical interactions of MET


Enzymatic interactions of MET


Regulatory relationships of MET


Other interactions of MET

  • CD44 is required for two consecutive steps in HGF/c-Met signaling [28].
  • We conclude that Ras and Rac act downstream of the SF/HGF receptor p190Met to mediate cell spreading but that an additional signal is required to induce scattering [29].
  • FAP68 binding to Met requires the last 30 amino acids of the C-terminal tail, which are unique to the HGF receptor [15].
  • Both VEGF receptor-2 and HGF receptor proteins were detected mainly in posterior portions of the membrane as well as in vessel walls and along the retinal interface where angiogenesis was active [30].
  • In our in vitro model of CRC migration and invasion, uPA and uPAR appear to be downstream of IGF-IR and c-Met and are required for migration and invasion [25].

Analytical, diagnostic and therapeutic context of MET


  1. Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met. van der Voort, R., Taher, T.E., Wielenga, V.J., Spaargaren, M., Prevo, R., Smit, L., David, G., Hartmann, G., Gherardi, E., Pals, S.T. J. Biol. Chem. (1999) [Pubmed]
  2. Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer. Wielenga, V.J., van der Voort, R., Taher, T.E., Smit, L., Beuling, E.A., van Krimpen, C., Spaargaren, M., Pals, S.T. Am. J. Pathol. (2000) [Pubmed]
  3. Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Maulik, G., Shrikhande, A., Kijima, T., Ma, P.C., Morrison, P.T., Salgia, R. Cytokine Growth Factor Rev. (2002) [Pubmed]
  4. Clinical significance of CXC chemokine receptor-4 and c-Met in childhood rhabdomyosarcoma. Diomedi-Camassei, F., McDowell, H.P., De Ioris, M.A., Uccini, S., Altavista, P., Raschellà, G., Vitali, R., Mannarino, O., De Sio, L., Cozzi, D.A., Donfrancesco, A., Inserra, A., Callea, F., Dominici, C. Clin. Cancer Res. (2008) [Pubmed]
  5. Hepatocyte growth factor/scatter factor and its receptor c-Met are overexpressed and associated with an increased microvessel density in malignant pleural mesothelioma. Tolnay, E., Kuhnen, C., Wiethege, T., König, J.E., Voss, B., Müller, K.M. J. Cancer Res. Clin. Oncol. (1998) [Pubmed]
  6. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Ponzetto, C., Bardelli, A., Zhen, Z., Maina, F., dalla Zonca, P., Giordano, S., Graziani, A., Panayotou, G., Comoglio, P.M. Cell (1994) [Pubmed]
  7. The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Petrelli, A., Gilestro, G.F., Lanzardo, S., Comoglio, P.M., Migone, N., Giordano, S. Nature (2002) [Pubmed]
  8. Radiation stimulates HGF receptor/c-Met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and MAP kinase activity in pancreatic cancer cells. Qian, L.W., Mizumoto, K., Inadome, N., Nagai, E., Sato, N., Matsumoto, K., Nakamura, T., Tanaka, M. Int. J. Cancer (2003) [Pubmed]
  9. CD44 stimulation by fragmented hyaluronic acid induces upregulation and tyrosine phosphorylation of c-Met receptor protein in human chondrosarcoma cells. Suzuki, M., Kobayashi, H., Kanayama, N., Nishida, T., Takigawa, M., Terao, T. Biochim. Biophys. Acta (2002) [Pubmed]
  10. CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins. Fujisaki, T., Tanaka, Y., Fujii, K., Mine, S., Saito, K., Yamada, S., Yamashita, U., Irimura, T., Eto, S. Cancer Res. (1999) [Pubmed]
  11. Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions. Hiscox, S., Jordan, N.J., Jiang, W., Harper, M., McClelland, R., Smith, C., Nicholson, R.I. Endocr. Relat. Cancer (2006) [Pubmed]
  12. Paracrine regulation of germinal center B cell adhesion through the c-met-hepatocyte growth factor/scatter factor pathway. van der Voort, R., Taher, T.E., Keehnen, R.M., Smit, L., Groenink, M., Pals, S.T. J. Exp. Med. (1997) [Pubmed]
  13. Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Dong, G., Chen, Z., Li, Z.Y., Yeh, N.T., Bancroft, C.C., Van Waes, C. Cancer Res. (2001) [Pubmed]
  14. Regulation of c-Met-dependent gene expression by PTEN. Abounader, R., Reznik, T., Colantuoni, C., Martinez-Murillo, F., Rosen, E.M., Laterra, J. Oncogene (2004) [Pubmed]
  15. Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor. Grisendi, S., Chambraud, B., Gout, I., Comoglio, P.M., Crepaldi, T. J. Biol. Chem. (2001) [Pubmed]
  16. The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. Graziani, A., Gramaglia, D., Cantley, L.C., Comoglio, P.M. J. Biol. Chem. (1991) [Pubmed]
  17. Increase in hepatocyte growth factor receptor tyrosine kinase activity in renal carcinoma cells is associated with increased motility partly through phosphoinositide 3-kinase activation. Nakamura, T., Kanda, S., Yamamoto, K., Kohno, T., Maeda, K., Matsuyama, T., Kanetake, H. Oncogene (2001) [Pubmed]
  18. CD151 forms a functional complex with c-Met in human salivary gland cancer cells. Klosek, S.K., Nakashiro, K., Hara, S., Shintani, S., Hasegawa, H., Hamakawa, H. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  19. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. Schaeper, U., Gehring, N.H., Fuchs, K.P., Sachs, M., Kempkes, B., Birchmeier, W. J. Cell Biol. (2000) [Pubmed]
  20. HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells. Davies, G., Jiang, W.G., Mason, M.D. Int. J. Mol. Med. (2001) [Pubmed]
  21. Potent blockade of hepatocyte growth factor-stimulated cell motility, matrix invasion and branching morphogenesis by antagonists of Grb2 Src homology 2 domain interactions. Atabey, N., Gao, Y., Yao, Z.J., Breckenridge, D., Soon, L., Soriano, J.V., Burke, T.R., Bottaro, D.P. J. Biol. Chem. (2001) [Pubmed]
  22. Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL. Sakkab, D., Lewitzky, M., Posern, G., Schaeper, U., Sachs, M., Birchmeier, W., Feller, S.M. J. Biol. Chem. (2000) [Pubmed]
  23. Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated beta-catenin. Herynk, M.H., Tsan, R., Radinsky, R., Gallick, G.E. Clin. Exp. Metastasis (2003) [Pubmed]
  24. Regulation of adhesion and migration in the germinal center microenvironment. Pals, S.T., Taher, T.E., van der Voort, R., Smit, L., Keehnen, R.M. Cell Adhes. Commun. (1998) [Pubmed]
  25. Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor. Bauer, T.W., Fan, F., Liu, W., Johnson, M., Parikh, N.U., Parry, G.C., Callahan, J., Mazar, A.P., Gallick, G.E., Ellis, L.M. Ann. Surg. (2005) [Pubmed]
  26. Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells. Hara, S., Nakashiro, K., Klosek, S.K., Ishikawa, T., Shintani, S., Hamakawa, H. Oral Oncol. (2006) [Pubmed]
  27. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Abounader, R., Laterra, J. Neuro-oncology (2005) [Pubmed]
  28. CD44 is required for two consecutive steps in HGF/c-Met signaling. Orian-Rousseau, V., Chen, L., Sleeman, J.P., Herrlich, P., Ponta, H. Genes Dev. (2002) [Pubmed]
  29. Regulation of scatter factor/hepatocyte growth factor responses by Ras, Rac, and Rho in MDCK cells. Ridley, A.J., Comoglio, P.M., Hall, A. Mol. Cell. Biol. (1995) [Pubmed]
  30. Vascular endothelial growth factor and hepatocyte growth factor levels are differentially elevated in patients with advanced retinopathy of prematurity. Lashkari, K., Hirose, T., Yazdany, J., McMeel, J.W., Kazlauskas, A., Rahimi, N. Am. J. Pathol. (2000) [Pubmed]
  31. Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase. Gandino, L., Longati, P., Medico, E., Prat, M., Comoglio, P.M. J. Biol. Chem. (1994) [Pubmed]
  32. Amplification and overexpression of the hepatocyte growth factor receptor (HGFR/MET) in rat DMBA sarcomas. Helou, K., Wallenius, V., Qiu, Y., Ohman, F., Ståhl, F., Klinga-Levan, K., Kindblom, L.G., Mandahl, N., Jansson, J.O., Levan, G. Oncogene (1999) [Pubmed]
  33. C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Lengyel, E., Prechtel, D., Resau, J.H., Gauger, K., Welk, A., Lindemann, K., Salanti, G., Richter, T., Knudsen, B., Vande Woude, G.F., Harbeck, N. Int. J. Cancer (2005) [Pubmed]
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