Sos-mediated cross activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis

Mammalian cells contain three closely related ras genes, H-ras, K-ras and N-ras. Although, in a given tumor type, oncogenic mutations are selectively observed in only one of the ras genes, the acquisition of the transformed phenotype has been shown to require the contribution of the normal products of the other ras genes. Here we demonstrate that oncogenic K-Ras promotes the activation of wild type H- and N-Ras. This activation is mediated by oncogenic K-Ras-dependent allosteric stimulation of Sos and confers a growth advantage to oncogenic K-Ras harboring cancer cells. These findings underscore the complementary functions of oncogenic and wild type Ras in tumor cells and identify a potential new targeting strategy for Ras-driven tumors.