Different point mutations in the met oncogene elicit distinct biological properties

Abstract

The MET proto-oncogene, encoding the tyrosine kinase receptor for HGF, controls genetic programs leading to cell growth, invasiveness, and protection from apoptosis. Recently, MET mutations have been identified in hereditary and sporadic forms of papillary renal carcinoma (PRC). Introduction of different naturally occurring mutations into the MET cDNA results in the acquisition of distinct biochemical and biological properties of transfected cells. Some mutations result in a high increase in tyrosine kinase activity and confer transforming ability in focus forming assays. These mutants hyperactivate the Ras signaling pathway. Other mutations are devoid of transforming potential but are effective in inducing protection from apoptosis and sustaining anchorage-independent growth. These Met(PRC) receptors interact more efficiently with the intracellular transducer Pi3Kinase. The reported results show that MET(PRC) mutations can be responsible for malignant transformation through different mechanisms, either by increasing the growth ability of cells or by protecting cells from apoptosis and allowing accumulation of other genetic lesions.-Giordano, S., Maffe, A., Williams, T. A., Artigiani, S., Gual, P., Bardelli, A., Basilico, C., Michieli, P., Comoglio, P. M. Different point mutations in the met oncogene elicit distinct biological properties.

Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas

“…The Y1230C mutation was shown to be oncogenic Michieli et al, 1999), but in particular to be very eective in inducing anchorageindependent growth and invasive phenotype in transfected cells (Giordano et al, 2000). Here we show that the MET Y1235D mutant stimulates epithelial cells to invade reconstituted basement membrane.…”

“…In particular, the MET Y1230C mutant receptor was shown to be very eective in inducing anchorage-independent growth and an invasive phenotype in transfected cells (Giordano et al, 2000).…”

The shadow of death on the MET tyrosine kinase receptor

“…Indeed, cells expressing the activated mutant forms of MET found in human cancer are more resistant to apoptosis. 97 Conversely, in MET-dependent transformed cells, the silencing of the receptor induced apoptotic cell death and reduction of tumour growth. 98,99 The mechanism of dependence through caspase cleavages can have important consequences on tumour progression.…”

The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants

“…Four mutated variants that are positioned in different functional locations of the Met kinase were studied: H1112Y -ATP-binding site, L1213V -hinge region, Y1248H -activation loop and M1268T -p þ 1 loop. All of these mutations cause constitutive Met phosphorylation and have been implicated in various transformation activities (Jeffers et al, 1997(Jeffers et al, , 1998Giordano et al, 2000). Suggested specific roles for part of these mutations have already been proposed (Miller et al, 2001;Danilkovitch-Miagkova and Zbar, 2002).…”