The role of ras GTPase activating protein in human tumorigenesis

Abnormal signal transduction involving activated ras genes plays a major role in the development of a variety of tumors. Ras GTPase-activating protein (rasGAP) is a major contributor to the downregulation of ras by facilitating GTP hydrolysis of activated ras. In addition, GAP participates in the downstream effector system of the ras signaling pathway. Thus, depending on the precise genetic alteration, its location within the gene and the effects it exerts on protein function, rasGAP can theoretically function as either an oncogene or as a tumor suppressor gene. The putative role that rasGAP plays in human tumorigenesis is further emphasized by two lines of indirect evidence. First, mutations within the C-terminal SH2 region of rasGAP in a subset of basal cell carcinomas were demonstrated. These are presumably activating mutations and therefore confer a direct oncogenic potential to rasGAP. Second, an inverse correlation between rasGAP protein expression and the invasive/malignant potential in human trophoblastic tumors was shown. Thus, in these latter tumors rasGAP functions as an apparent tumor suppressor gene. Employing combined laboratory techniques and approaches to a variety of human tumors will further define the role of rasGAP in tumorigenesis, provide insight into the mode of action of rasGAP and structure-function relationships. Furthermore, it will help in establishing genotype-phenotype correlations and potentially may lead to a pharmacological approach to treating choriocarcinomas.