| Structural highlights
Disease
[MET_HUMAN] Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. Note=Defects in MET may be associated with gastric cancer. Defects in MET are a cause of hepatocellular carcinoma (HCC) [MIM:114550].[1] Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:605074]. It is a subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into common renal cell carcinoma (clear cell, non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.[2] [3] [4] [5] [6] Note=A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes. Note=MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.[7]
Function
[MET_HUMAN] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells.[8] [9] [10] Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells.[11] [12] [13]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.
c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations.,Bellon SF, Kaplan-Lefko P, Yang Y, Zhang Y, Moriguchi J, Rex K, Johnson CW, Rose PE, Long AM, O'Connor AB, Gu Y, Coxon A, Kim TS, Tasker A, Burgess TL, Dussault I J Biol Chem. 2008 Feb 1;283(5):2675-83. Epub 2007 Nov 30. PMID:18055465[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS, Lee SH, Yoo NJ, Jang JJ, Pack S, Zhuang Z, Schmidt L, Zbar B, Lee JY. Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res. 1999 Jan 15;59(2):307-10. PMID:9927037
- ↑ Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997 May;16(1):68-73. PMID:9140397 doi:10.1038/ng0597-68
- ↑ Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Vande Woude G, Neumann H, Walther M, Linehan WM, Zbar B. Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res. 1998 Apr 15;58(8):1719-22. PMID:9563489
- ↑ Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N, Walther MM, Choyke P, Linehan WM, Zbar B. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol. 1999 Aug;155(2):517-26. PMID:10433944 doi:10.1016/S0002-9440(10)65147-4
- ↑ Olivero M, Valente G, Bardelli A, Longati P, Ferrero N, Cracco C, Terrone C, Rocca-Rossetti S, Comoglio PM, Di Renzo MF. Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family. Int J Cancer. 1999 Aug 27;82(5):640-3. PMID:10417759
- ↑ Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M, Lubensky I, Neumann HP, Brauch H, Decker J, Vocke C, Brown JA, Jenkins R, Richard S, Bergerheim U, Gerrard B, Dean M, Linehan WM, Zbar B. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene. 1999 Apr 8;18(14):2343-50. PMID:10327054 doi:10.1038/sj.onc.1202547
- ↑ Stella GM, Benvenuti S, Gramaglia D, Scarpa A, Tomezzoli A, Cassoni P, Senetta R, Venesio T, Pozzi E, Bardelli A, Comoglio PM. MET mutations in cancers of unknown primary origin (CUPs). Hum Mutat. 2011 Jan;32(1):44-50. doi: 10.1002/humu.21374. Epub 2010 Nov 9. PMID:20949619 doi:10.1002/humu.21374
- ↑ Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991 Feb 15;251(4995):802-4. PMID:1846706
- ↑ Nusrat A, Parkos CA, Bacarra AE, Godowski PJ, Delp-Archer C, Rosen EM, Madara JL. Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium. J Clin Invest. 1994 May;93(5):2056-65. PMID:8182137 doi:http://dx.doi.org/10.1172/JCI117200
- ↑ Higuchi T, Orita T, Katsuya K, Yamasaki Y, Akiyama K, Li H, Yamamoto T, Saito Y, Nakamura M. MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met. Mol Cell Biol. 2004 Sep;24(17):7456-68. PMID:15314156 doi:10.1128/MCB.24.17.7456-7468.2004
- ↑ Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991 Feb 15;251(4995):802-4. PMID:1846706
- ↑ Nusrat A, Parkos CA, Bacarra AE, Godowski PJ, Delp-Archer C, Rosen EM, Madara JL. Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium. J Clin Invest. 1994 May;93(5):2056-65. PMID:8182137 doi:http://dx.doi.org/10.1172/JCI117200
- ↑ Higuchi T, Orita T, Katsuya K, Yamasaki Y, Akiyama K, Li H, Yamamoto T, Saito Y, Nakamura M. MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met. Mol Cell Biol. 2004 Sep;24(17):7456-68. PMID:15314156 doi:10.1128/MCB.24.17.7456-7468.2004
- ↑ Bellon SF, Kaplan-Lefko P, Yang Y, Zhang Y, Moriguchi J, Rex K, Johnson CW, Rose PE, Long AM, O'Connor AB, Gu Y, Coxon A, Kim TS, Tasker A, Burgess TL, Dussault I. c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations. J Biol Chem. 2008 Feb 1;283(5):2675-83. Epub 2007 Nov 30. PMID:18055465 doi:10.1074/jbc.M705774200
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