Analysis of 501 melanoma exomes revealed RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas.,Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration.,RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival.,These findings reveal RASA2 inactivation as a melanoma driver and highlight the importance of Ras GAPs in cancer.
Up to one third of human melanomas are characterized by an oncogenic mutation in the gene encoding the small GTPase NRAS.,Ras proteins activate three primary classes of effectors: Rafs, PI3Ks, and RalGEFs.,In melanomas lacking NRAS mutations, the first two effectors can still be activated vis-à-vis oncogenic BRAF mutations coupled with a loss of the PI3K negative regulator PTEN.,This suggests that Ras effectors promote melanoma, regardless of whether they are activated by oncogenic NRas.,The only major Ras effector pathway not explored for its role in melanoma is the RalGEF-Ral pathway, in which the Ras activation of RalGEFs converts the small GTPases RalA and RalB to an active GTP-bound state.,We report that RalA is activated in a number of human melanoma cancer cell lines harboring an oncogenic NRAS allele, an oncogenic BRAF allele, or wild type NRAS and BRAF alleles.,Furthermore, shRNA-mediated knock down of RalA, and to a lesser extent RalB, inhibited the tumorigenic growth of melanoma cell lines having these three genotypes.,Thus, as is the case for Raf and PI3K signaling, Rals also contribute to melanoma tumorigenesis.