Mm. Santoro et al., The Ron oncogenic activity induced by the MEN2B-like substitution overcomes the requirement for the multifunctional docking site, ONCOGENE, 19(45), 2000, pp. 5208-5211
Oncogenic activation of the Ron tyrosine kinase (Macrophage Stimulating Pro
tein receptor) relies on substitutions of two highly conserved residues in
the catalytic domain (D1232V and M1254T), which result in ligand-independen
t activation of the receptor, in vivo tumorigenesis and metastasis. We show
here that the Y/F conversion of the Y-1317 residue in the kinase domain im
pairs tumorigenic and metastatic properties of Ron activated by the MEN2B-l
ike mutation (Ron(M1254T)), but not by other two oncogenic substitutions, F
urthermore, Ron(M1254T) lacking the multifunctional docking site retains tr
ansforming and metastatic activity, These data reveal that the transforming
activity of Ron(M1254T) mutant is dependent on Y-1317 phosphorylation, sug
gesting a shift in intramolecular substrate specificity. Consistently, a sh
ift of Ron(M1254T) kinase substrate specificity was observed by in vitro pe
ptide phosphorylation assays and in vitro receptor autophosphorylation, The
Y-1317 phosphorylation elicits by itself activation of PI-3K/Akt and MAPK
signalling pathways, Our data indicate that the accomplishment of the full
oncogenic phenotype of Ron(M1254T) requires the phosphorylation both of the
canonical C-terminal docking site and of the unique Y-1317 residue in the
tyrosine kinase domain.