Over-expression of Rap2a inhibits glioma migration and invasion by down-regulating p-AKT

Ras-oncogenic pathway contributes to the pathogenesis of various tumours in humans, in which mutations of three canonical genes including H-Ras, N-Ras and K-Ras are the most common events. Dysregulation of Ras signalling can be tumourigenic, especially gliomas of the central nervous system. Rap proteins are members of the small GTPase superfamily that involved in many biological processes. However, it remains largely unclear as to whether and how Rap proteins are involved in the development of multiple gliomas. We found that the levels of the protein Rap2a and the activity of Rap2a (GTP-Rap2a) were weakly expressed in glioma tissues. Overexpressed Rap2a significantly inhibited the migration and invasion of glioma cells with an increase of GTP-Rap2a. Overexpression of the dominant-active (DA-Rap2a), but not the dominant-negative (DN-Rap2a) form of Rap2a, also similarly inhibited the migration and invasion of glioma cells by reducing the phosphorylation level of AKT. In contrast, downregulation of Rap2a promoted glioma migration and invasion, and raised the phosphorylation level of AKT, whereas these effects were inhibited by PI3K-specific inhibitor, LY294002. Thus unlike the other family members of Ras, Rab2a probably serves as a tumour suppressor in the pathogenesis of glioma.