Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth.
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. METPRC 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 METPRC 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 (YpVNV) inhibits invasive growth induced by METPRC 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.
Bardelli
A
A
Institute for Cancer Research and Treatment, University of Torino, School of Medicine 10060, Candiolo, Italy. abardelli@ircc.unito.it
Longati
P
P
Gramaglia
D
D
Basilico
C
C
Tamagnone
L
L
Giordano
S
S
Ballinari
D
D
Michieli
P
P
Comoglio
P M
PM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002291:Carcinoma, Papillary / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003001:Cloning, Molecular; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D019000:Phosphotyrosine; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D015398:Signal Transduction; D014162:Transfection
D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D019000:Phosphotyrosine; D019859:Proto-Oncogene Proteins c-met