METPRC mutations in the Ron receptor result in upregulation of tyrosine kinase activity and acquisition of oncogenic potential

Ron and Met are structurally related receptor tyrosine kinases that elicit a complex biological response leading to invasive growth. Naturally occurri ng point mutations activate the Met kinase in papillary renal carcinomas (M ETPRC mutations). By site-directed mutagenesis, we generated homologous ami no acid substitutions in the Ron kinase domain and analyzed the biochemical and biological properties of the mutant receptors. Among the mutations stu died, D1232H and M1254T displayed transforming activity in NIH3T3 cells, in ducing focus formation and anchorage-independent growth. The D1232H and M12 54T substitutions resulted in increased Ron autophosphorylation both in viv o and in vitro and constitutive binding to intracellular signal transducers . Both mutations yielded a dramatic increase in catalytic efficiency, indic ating a direct correlation between kinase activity and oncogenic potential. Molecular modeling of the Ron D1232H mutation suggests that this single am ino acid substitution favors the transition of the kinase from the inactive to the active state. These data demonstrate that point mutations can confe r transforming activity to the Ron receptor and show that RON is a potentia l oncogene. (C) 1999 Wiley-Liss, Inc.