Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins

TC21 is a Ras-like GTPase with high oncogenic potential that is found mutat ed in some human tumors and overexpressed in breast cancer cell lines. We h ave conducted cellular and biochemical studies in order to understand the r ole of this protein in signal transduction and to unveil the signaling elem ents that participate in the TC21 pathway. Using gene transfer experiments, we demonstrate here that the TC21 oncogene can induce both cellular transf ormation in mouse fibroblasts and neuronal-like differentiation in rat PC12 cells. Interestingly, the proto-oncogenic version of TC21 shows also a low er, but significant, activity in both biological processes. We also demonst rate that the similarity of the cellular responses induced by TC21 and Ras derive from the utilization of overlapping pathways. Thus, the exchange of guanosine nucleotides in wild type TC21 is catalyzed by Ras exchange factor s. Moreover, TC21 binds physically to c-Raf-1 in a GTP-dependent manner. Fi nally, overexpression of TC21(G23V) in NIH3T3 cells results in the activati on of c-Raf-1 and the MAPK and the JNK branches of serine/threonine cascade s. From these results, we conclude that TC21 promotes Ras-like responses in diverse cell types due to the use of overlapping, if not identical, signal ing elements of the Ras oncogenic pathway.