TY - JOUR
T1 - Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth
AU - Bardelli, Alberto
AU - Longati, Paola
AU - Gramaglia, Daniela
AU - Basilico, Cristina
AU - Tamagnone, Luca
AU - Giordano, Silvia
AU - Ballinari, Dario
AU - Michieli, Paolo
AU - Comoglio, Paolo M.
PY - 1998/11/24
Y1 - 1998/11/24
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.95.24.14379
DO - 10.1073/pnas.95.24.14379
M3 - Article
C2 - 9826708
AN - SCOPUS:0032564368
VL - 95
SP - 14379
EP - 14383
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 24
ER -