Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth

Luca Tamagnone, Alberto Bardelli, Paola Longati, Daniela Gramaglia, Cristina Basilico, Silvia Giordano, Dario Ballinari, Paolo Michieli, Paolo M. Comoglio

Risultato della ricerca: Contributo in rivistaArticolo in rivista

87 Citazioni (Scopus)


The assumption that genes encoding tyrosine kinase receptors could play a role in human cancers has been confirmed by the identification of oncogenic mutations in the kinase domain of RET and KIT. Recently, homologous residues were found mutated in MET, in papillary renal carcinomas (PRCs). The link coupling these genetic lesions to cellular transformation is still unclear. MET(PRC) mutations result in increased kinase activity and - in some instances, i.e., M1250T substitution - in changes in substrate specificity. A direct correlation occurs between the transforming potential of MET(PRC) mutants and their ability to constitutively associate with signal transducers through two phosphorylated tyrosines (Y1349VHVNATY1356VNV) located in the receptor tail. Substitution of these 'docking tyrosines' with phenylalanines leaves unaffected the altered properties of the kinase but abrogates transformation and invasiveness in vitro. Uncoupling the receptor from signal transducers with a tyrosine-phosphorylated peptide derivative (Y(p)VNV) inhibits invasive growth induced by MET(PRC) mutants. These data indicate that constitutive receptor coupling to downstream signal transducers is a key mechanism in neoplastic transformation driven by mutated MET and suggest a therapeutic strategy to target neoplastic diseases associated with this oncogene.
Lingua originaleEnglish
pagine (da-a)14379-14383
Numero di pagine5
RivistaProceedings of the National Academy of Sciences of the United States of America
Stato di pubblicazionePubblicato - 1998


  • Multidisciplinary

Fingerprint Entra nei temi di ricerca di 'Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth'. Insieme formano una fingerprint unica.

Cita questo