An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer

The RAS pathway is one of the most commonly deregulated pathways in human cancer. Mutations in RAS genes occur in nearly 30% of all human tumors. However in some tumor types RAS mutations are conspicuously absent or rare, despite the fact that RAS and downstream effector pathways are hyperactivated. Recently, RAS GTPase Activating Proteins (RAS GAPs) have emerged as an expanding class of tumor suppressors that, when inactivated, provide an alternative mechanism of activating RAS. RAS GAPs normally turn off RAS by catalyzing the hydrolysis of RAS-GTP. As such, the loss of a RAS GAP would be expected to promote excessive RAS activation. Indeed, this is the case for the NF1 gene, which plays an established role in a familial tumor predisposition syndrome and a variety of sporadic cancers. However, there are 13 additional RAS GAP family members in the human genome. We are only now beginning to understand why there are so many RAS GAPs, how they differentially function, and what their potential role(s) in human cancer are. This review will focus on our current understanding of RAS GAPs in human disease and will highlight important outstanding questions.