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

โœ Scribed by Tracy A. Williams; Paola Longati; Luisa Pugliese; Philippe Gual; Alberto Bardelli; Paolo Michieli

Publisher
John Wiley and Sons
Year
1999
Tongue
English
Weight
218 KB
Volume
181
Category
Article
ISSN
0021-9541

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โœฆ Synopsis

Ron and Met are structurally related receptor tyrosine kinases that elicit a complex biological response leading to invasive growth. Naturally occurring point mutations activate the Met kinase in papillary renal carcinomas (MET PRC mutations). By site-directed mutagenesis, we generated homologous amino acid substitutions in the Ron kinase domain and analyzed the biochemical and biological properties of the mutant receptors. Among the mutations studied, D 1232 H and M 1254 T displayed transforming activity in NIH3T3 cells, inducing focus formation and anchorage-independent growth. The D 1232 H and M 1254 T substitutions resulted in increased Ron autophosphorylation both in vivo and in vitro and constitutive binding to intracellular signal transducers. Both mutations yielded a dramatic increase in catalytic efficiency, indicating a direct correlation between kinase activity and oncogenic potential. Molecular modeling of the Ron D 1232 H mutation suggests that this single amino acid substitution favors the transition of the kinase from the inactive to the active state. These data demonstrate that point mutations can confer transforming activity to the Ron receptor and show that RON is a potential oncogene.

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