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Gene Review

Met  -  met proto-oncogene

Mus musculus

Synonyms: AI838057, HGF, HGF receptor, HGF/SF receptor, HGFR, ...
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Disease relevance of Met

  • These findings are consistent with the possibility that HGF-Met protein interaction is one of the molecular mechanisms promoting the vascularization of papillary carcinoma of the thyroid [1].
  • We investigated the biochemical and biological effects of the tyrosine kinase inhibitor RPI-1 on the human lung cancer cell lines H460 and N592, which express constitutively active Met [2].
  • Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model [3].
  • We also identified an Egr-1-binding site in the mouse CD44 gene promoter that accounts for its responsiveness to HGF/SF in melanoma cells [4].
  • It is also known that delivery of the human HGF gene cloned in a plasmid under a CMV promoter results in hepatomegaly in mice [5].

Psychiatry related information on Met


High impact information on Met


Chemical compound and disease context of Met

  • Rat HGF cDNA, expressed under the control of a cytomegalovirus promoter, was transfected together with the neomycin resistance gene (PSV2neo) into MLE-10 cells by the calcium phosphate method, and propagated G418-resistant colonies were harvested colony by colony [12].
  • In vitro, HGF expression was evaluated in isolated murine ATII cells and in 12 ADC cell lines, and we found that nicotine activated HGF expression in ATII cells and lung cancer cells [13].
  • Analysis of genomic DNA of 126 lung adenocarcinoma patients for the Met juxtamembrane domain revealed the same Arg/Cys variation at the mouse homologous position in one patient; two other patients carried additional variants in the same domain, suggesting a potential role for rare MET juxtamembrane variants in human lung cancer [14].
  • Similar HGF/SF treatment of cysts derived from cells expressing NH2-terminal deleted beta-catenins resulted in cells that proliferated but formed cell aggregates (polyps) within the cyst rather than tubules [15].
  • Administration of LPS + GalN, without HGF, rapidly led to massive hepatocyte apoptosis and severe liver injury, and all mice died of hepatic failure within 8 hours [16].

Biological context of Met

  • The transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo [17].
  • The Met mutation also increased sympathetic neuroblast apoptosis in vivo [18].
  • Here, we use conditional mutagenesis in mice to analyze the function of Met during liver regeneration, using the Mx-cre transgene to introduce the mutation in the adult [19].
  • Comparison of signal transduction pathways in control and mutant livers indicates that Met and other signaling receptors cooperate to fully activate particular signaling molecules, for instance, the protein kinase Akt [19].
  • Analysis of cell cycle progression of hepatocytes in conditional Met mutant mice indicates a defective exit from quiescence and diminished entry into S phase [19].

Anatomical context of Met

  • Similar results were obtained with NIH 3T3 cells expressing the fusion protein Trk-Met and stimulated with nerve growth factor, the Trk ligand [20].
  • Moreover, late passage fibroblast cell lines established from p53-deficient animals overexpress Met and can be tumorigenic in athymic nude mice, suggesting that progression occurs in vitro [21].
  • Addition of heparin to HSGAG-deficient CHO cells not only restored ligand binding, but also increased ligand-dependent Met tyrosine phosphorylation and c-fos expression [22].
  • NGF-stimulation of mouse fibroblasts expressing tagged versions of both Trk-Met and Gab1 with NGF resulted in anchorage-independent growth and enhanced invasiveness [23].
  • HGF greatly enhanced the neurite outgrowth of NGF-dependent sympathetic neurons throughout development [18].

Associations of Met with chemical compounds

  • Heparin binding and oligomerization of hepatocyte growth factor/scatter factor isoforms. Heparan sulfate glycosaminoglycan requirement for Met binding and signaling [22].
  • A C2 clone expressing simultaneously both h-met and h-HGF/SF is able to grow in soft agar and shows a decrease in myogenic potential comparable to that promoted by p65(tpr-met) kinase [24].
  • In this study, we demonstrate that the amino-terminal (N) domain retains the heparin-binding properties of full-length HGF/SF [22].
  • HGF/SF consists of a series of structural units, including an amino-terminal segment with a hairpin loop, four kringle domains, and a serine protease-like region [22].
  • Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine [25].

Enzymatic interactions of Met

  • HGF is secreted as an inactive zymogen and must be cleaved by a serine protease to initiate Met signaling [26].

Regulatory relationships of Met

  • Thus, the loss of wild-type p53 appears to greatly enhance the opportunity for inappropriate Met expression [21].
  • In both M23 and MM55 cells, HGF induces association with MET/HGFR and increased tyrosine phosphorylation of the SH2-domain containing proteins PI3K, GAP and NCK [27].
  • FGF-2 also induced HGF/SF polypeptide synthesis [28].
  • We now report that expression of the mutant presenilin-1 in these mice induces early and exaggerated increase in Par-4 expression in hippocampal neurons following glucose deprivation (an insult relevant to the pathogenesis of AD) [29].
  • Both HGF-induced DNA fragmentation and caspase-3 activity were completely inhibited by co-incubation with an inhibitor of caspase-3, Ac-DEVD-H [30].

Other interactions of Met


Analytical, diagnostic and therapeutic context of Met


  1. Papillary carcinoma of the thyroid: evidence for a role for hepatocyte growth factor (HGF) in promoting tumour angiogenesis. Scarpino, S., D'Alena, F.C., Di Napoli, A., Ballarini, F., Prat, M., Ruco, L.P. J. Pathol. (2003) [Pubmed]
  2. Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1. Cassinelli, G., Lanzi, C., Petrangolini, G., Tortoreto, M., Pratesi, G., Cuccuru, G., Laccabue, D., Supino, R., Belluco, S., Favini, E., Poletti, A., Zunino, F. Mol. Cancer Ther. (2006) [Pubmed]
  3. Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model. Yu, Y., Merlino, G. Cancer Res. (2002) [Pubmed]
  4. Hepatocyte growth factor/scatter factor induces feedback up-regulation of CD44v6 in melanoma cells through Egr-1. Recio, J.A., Merlino, G. Cancer Res. (2003) [Pubmed]
  5. Activation of Wnt/beta-catenin pathway during hepatocyte growth factor-induced hepatomegaly in mice. Apte, U., Zeng, G., Muller, P., Tan, X., Micsenyi, A., Cieply, B., Dai, C., Liu, Y., Kaestner, K.H., Monga, S.P. Hepatology (2006) [Pubmed]
  6. Rapid growth of invasive metastatic melanoma in carcinogen-treated hepatocyte growth factor/scatter factor-transgenic mice carrying an oncogenic CDK4 mutation. Tormo, D., Ferrer, A., Gaffal, E., Wenzel, J., Basner-Tschakarjan, E., Steitz, J., Heukamp, L.C., Gütgemann, I., Buettner, R., Malumbres, M., Barbacid, M., Merlino, G., Tüting, T. Am. J. Pathol. (2006) [Pubmed]
  7. Expression of hepatocyte growth factor/scatter factor and its receptor, MET, suggests roles in human embryonic organogenesis. Kolatsi-Joannou, M., Moore, R., Winyard, P.J., Woolf, A.S. Pediatr. Res. (1997) [Pubmed]
  8. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Trusolino, L., Bertotti, A., Comoglio, P.M. Cell (2001) [Pubmed]
  9. Early specification of limb muscle precursor cells by the homeobox gene Lbx1h. Schäfer, K., Braun, T. Nat. Genet. (1999) [Pubmed]
  10. Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development. Maina, F., Casagranda, F., Audero, E., Simeone, A., Comoglio, P.M., Klein, R., Ponzetto, C. Cell (1996) [Pubmed]
  11. Mechanism of met oncogene activation. Park, M., Dean, M., Cooper, C.S., Schmidt, M., O'Brien, S.J., Blair, D.G., Vande Woude, G.F. Cell (1986) [Pubmed]
  12. Hepatocyte growth factor transforms immortalized mouse liver epithelial cells. Kanda, H., Tajima, H., Lee, G.H., Nomura, K., Ohtake, K., Matsumoto, K., Nakamura, T., Kitagawa, T. Oncogene (1993) [Pubmed]
  13. Cigarette smoking induces overexpression of hepatocyte growth factor in type II pneumocytes and lung cancer cells. Chen, J.T., Lin, T.S., Chow, K.C., Huang, H.H., Chiou, S.H., Chiang, S.F., Chen, H.C., Chuang, T.L., Lin, T.Y., Chen, C.Y. Am. J. Respir. Cell Mol. Biol. (2006) [Pubmed]
  14. Met proto-oncogene juxtamembrane rare variations in mouse and humans: differential effects of Arg and Cys alleles on mouse lung tumorigenesis. Zaffaroni, D., Spinola, M., Galvan, A., Falvella, F.S., Pazzaglia, S., Saran, A., Mancuso, M.T., Galbiati, F., Pignatiello, C., Cabrera, W., Ibanez, O., Manenti, G., Dragani, T.A. Oncogene (2005) [Pubmed]
  15. Dynamics of beta-catenin interactions with APC protein regulate epithelial tubulogenesis. Pollack, A.L., Barth, A.I., Altschuler, Y., Nelson, W.J., Mostov, K.E. J. Cell Biol. (1997) [Pubmed]
  16. Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. Kosai, K., Matsumoto, K., Funakoshi, H., Nakamura, T. Hepatology (1999) [Pubmed]
  17. The transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo. Relaix, F., Polimeni, M., Rocancourt, D., Ponzetto, C., Schäfer, B.W., Buckingham, M. Genes Dev. (2003) [Pubmed]
  18. Multiple roles for hepatocyte growth factor in sympathetic neuron development. Maina, F., Hilton, M.C., Andres, R., Wyatt, S., Klein, R., Davies, A.M. Neuron (1998) [Pubmed]
  19. Met provides essential signals for liver regeneration. Borowiak, M., Garratt, A.N., Wüstefeld, T., Strehle, M., Trautwein, C., Birchmeier, C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  20. Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Xiao, G.H., Jeffers, M., Bellacosa, A., Mitsuuchi, Y., Vande Woude , G.F., Testa, J.R. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  21. Met proto-oncogene product is overexpressed in tumors of p53-deficient mice and tumors of Li-Fraumeni patients. Rong, S., Donehower, L.A., Hansen, M.F., Strong, L., Tainsky, M., Jeffers, M., Resau, J.H., Hudson, E., Tsarfaty, I., Vande Woude, G.F. Cancer Res. (1995) [Pubmed]
  22. Heparin binding and oligomerization of hepatocyte growth factor/scatter factor isoforms. Heparan sulfate glycosaminoglycan requirement for Met binding and signaling. Sakata, H., Stahl, S.J., Taylor, W.G., Rosenberg, J.M., Sakaguchi, K., Wingfield, P.T., Rubin, J.S. J. Biol. Chem. (1997) [Pubmed]
  23. Activation of the c-Met receptor complex in fibroblasts drives invasive cell behavior by signaling through transcription factor STAT3. Cramer, A., Kleiner, S., Westermann, M., Meissner, A., Lange, A., Friedrich, K. J. Cell. Biochem. (2005) [Pubmed]
  24. A natural hepatocyte growth factor/scatter factor autocrine loop in myoblast cells and the effect of the constitutive Met kinase activation on myogenic differentiation. Anastasi, S., Giordano, S., Sthandier, O., Gambarotta, G., Maione, R., Comoglio, P., Amati, P. J. Cell Biol. (1997) [Pubmed]
  25. Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine. Horiguchi, N., Takayama, H., Toyoda, M., Otsuka, T., Fukusato, T., Merlino, G., Takagi, H., Mori, M. Oncogene (2002) [Pubmed]
  26. Activation of hepatocyte growth factor (HGF) by endogenous HGF activator is required for metanephric kidney morphogenesis in vitro. van Adelsberg, J., Sehgal, S., Kukes, A., Brady, C., Barasch, J., Yang, J., Huan, Y. J. Biol. Chem. (2001) [Pubmed]
  27. Hepatocyte growth factor-induced signal transduction in two normal mouse epithelial cell lines. Johnson, M., Kochhar, K., Nakamura, T., Iyer, A. Biochem. Mol. Biol. Int. (1995) [Pubmed]
  28. Fibroblast growth factor-2 induces hepatocyte growth factor/scatter factor expression in osteoblasts. Blanquaert, F., Delany, A.M., Canalis, E. Endocrinology (1999) [Pubmed]
  29. Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice. Xie, J., Chang, X., Zhang, X., Guo, Q. Brain Res. (2001) [Pubmed]
  30. Hepatocyte growth factor/scatter factor activates the apoptosis signaling pathway by increasing caspase-3 activity in sarcoma 180 cells. Arakaki, N., Kazi, J.A., Kazihara, T., Ohnishi, T., Daikuhara, Y. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  31. Hepatocyte growth factor/scatter factor is a motogen for interneurons migrating from the ventral to dorsal telencephalon. Powell, E.M., Mars, W.M., Levitt, P. Neuron (2001) [Pubmed]
  32. Genetic mapping of lung cancer modifier loci specifically affecting tumor initiation and progression. Manenti, G., Gariboldi, M., Fiorino, A., Zanesi, N., Pierotti, M.A., Dragani, T.A. Cancer Res. (1997) [Pubmed]
  33. The role of SF/HGF and c-Met in the development of skeletal muscle. Dietrich, S., Abou-Rebyeh, F., Brohmann, H., Bladt, F., Sonnenberg-Riethmacher, E., Yamaai, T., Lumsden, A., Brand-Saberi, B., Birchmeier, C. Development (1999) [Pubmed]
  34. Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Rong, S., Bodescot, M., Blair, D., Dunn, J., Nakamura, T., Mizuno, K., Park, M., Chan, A., Aaronson, S., Vande Woude, G.F. Mol. Cell. Biol. (1992) [Pubmed]
  35. Expression of the met receptor tyrosine kinase in muscle progenitor cells in somites and limbs is absent in Splotch mice. Yang, X.M., Vogan, K., Gros, P., Park, M. Development (1996) [Pubmed]
  36. HGF/SF increases tumor blood volume: a novel tool for the in vivo functional molecular imaging of Met. Tsarfaty, G., Stein, G.Y., Moshitch-Moshkovitz, S., Kaufman, D.W., Cao, B., Resau, J.H., Vande Woude, G.F., Tsarfaty, I. Neoplasia (2006) [Pubmed]
  37. Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Cornelison, D.D., Filla, M.S., Stanley, H.M., Rapraeger, A.C., Olwin, B.B. Dev. Biol. (2001) [Pubmed]
  38. Hepatocyte growth factor/scatter factor facilitates migration of GN-11 immortalized LHRH neurons. Giacobini, P., Giampietro, C., Fioretto, M., Maggi, R., Cariboni, A., Perroteau, I., Fasolo, A. Endocrinology (2002) [Pubmed]
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