Most of the proteins in the Ras-family proteins, including Ras, Rap and TC21, have been reported to be strong inhibitors of skeletal myogenesis. Here we show that R-Ras, another member of this family, promotes terminal dierentiation of C2C12 skeletal myoblasts. In contrast to Ras, which induced a markedly transformed phenotype of C2C12 cells, an activated mutant of R-Ras (R-Ras Q87L ) did not exhibit any inhibitory eect on the dierentiation of C2C12 cells, but enhanced the formation of multinucleated myotubes. Although R-Ras Q87L showed little eect on induction of two muscle-speci®c proteins, creatine kinase and myogenin, it prevented cell death during myoblast dierentiation, probably through Akt activation and Bcl-x L induction. Motility of C2C12 cells, which may be involved in fusion of myoblasts, was also stimulated by R-Ras
Q87L. Furthermore, we observed a transient activation of endogenous R-Ras during dierentiation of C2C12 cells. The ectopic expression of R-Ras GAP inhibited the dierentiation. These results suggest that R-Ras has a positive eect on the terminal dierentiation of myoblasts and may be involved in the program of skeletal myogenesis.