Smad3 deficiency inhibits v-ras-induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition

The ability of transforming growth factor-β (TGF-β) to modulate various effects on distinct cell lineages has been a central feature of its multi-faceted nature. The purpose of this study was to access the effects of deletion of a key TGF-β signal transducer, Smad3, on MAPK activation and v-Ras^Ha-transformation of primary mouse embryonic fibroblasts (MEFs). We observe reduced TGF-β1 and v-ras^Ha mediated activation of the JNK and ERK MAPK pathway upon ablation of Smad3. Further, Smad3-deficient MEFs demonstrate resistance to v-ras^Ha-induced transformation while the absence of Smad3 results in increased inhibition of farnesyl transferase activity. Taken together, these observations demonstrate that the absence of Smad3 protects fibroblasts from oncogenic transformation by (i) augmenting farnesyl transferase inhibition and (ii) suppressing the Ras - JNK MAPK pathway. These results provide new insights into the molecular mechanisms involved in v-Ras^Ha oncogene-induced mesenchymal phenotypic transformation.