Somatic mutations lead to an oncogenic deletion of met in lung cancer

Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of som...

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Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Ill.), 2006, Vol.66 (1), p.283-289
Main Authors:	KONG-BELTRAN, Monica, SESHAGIRI, Somasekar, SEVERIN, Christophe, RANGELL, Linda, SCHWALL, Ralph, AMLER, Lukas, WICKRAMASINGHE, Dineli, YAUCH, Robert, JIPING ZHA, WENJING ZHU, BHAWE, Kaumudi, MENDOZA, Nerissa, HOLCOMB, Thomas, PUJARA, Kanan, STINSON, Jeremy, LING FU
Format:	Article
Language:	eng
Subjects:	Alternative Splicing Animals Biological and medical sciences Carcinoma, Non-Small-Cell Lung - enzymology Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Cell Line, Tumor Colonic Neoplasms - enzymology Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Down-Regulation Enzyme Activation Exons Female Gene Deletion Humans Introns Lung Neoplasms - enzymology Lung Neoplasms - genetics Lung Neoplasms - metabolism Medical sciences Mice Mice, Nude Mitogen-Activated Protein Kinases - metabolism Mutation Phosphorylation Pneumology Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - biosynthesis Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-cbl - metabolism Proto-Oncogene Proteins c-met Receptors, Growth Factor - antagonists & inhibitors Receptors, Growth Factor - biosynthesis Receptors, Growth Factor - genetics Receptors, Growth Factor - metabolism Signal Transduction Tumors of the respiratory system and mediastinum Ubiquitin - metabolism
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Summary:	Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation-driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer.
ISSN:	0008-5472 1538-7445