CONSTITUTIVE ACTIVATION OF THE RON GENE PROMOTES INVASIVE GROWTH BUT NOT TRANSFORMATION

MET, RON, and SEA are members of a gene family encoding tyrosine kinas e receptors with distinctive properties, Besides mediating growth, the y control cell dissociation, motility (''scattering''), and formation of branching tubules. While there are transforming counterparts of MET and SEA, no oncogenic forms of RON have yet been identified. A chimer ic Tpr-Ron, mimicking the oncogenic form of Met (Tpr-Sea) was generate d to investigate its transforming potential. For comparison, a chimeri c Tpr-Sea was also constructed. Fusion with Tpr induced constitutive a ctivation of the Ron and Sea kinases. While Tpr-Sea was more efficient than Tpr-Met in transformation, Tpr-Ron did not transform NIH 3T3 cel ls. The differences in the transforming abilities of Tpr-Met and Tpr-R on were linked to the functional features of the respective tyrosine k inases using the approach of swapping subdomains. Kinetic analysis sho wed that the catalytic efficiency of Tpr-Ron is five times lower than that of Tpr-Met. Moreover, constitutive activation of Ron resulted in activation of the AP kinase signaling cascade approximately three time s lower than that attained by Tpr-Met. However, constitutive activatio n of Ron did induce a mitogenic-invasive a response, causing cell diss ociation, motility, and invasion of extracellular matrices. Tpr-Ron al so induced formation of long, unbranched tubules in tridimensional col lagen gels, These data show that RON has the potential to elicit a mot ile-invasive rather than a transformed phenotype.