FBS Colloquia No.193Cellular and Molecular Neurobiology Group

R-Ras small GTPase functions as a signaling hub that enables orchestral regulation of various cell functions

R-Ras is a ubiquitously expressed member of the Ras superfamily of small GTPases, which forms a distinct subfamily from classical Ras (i.e., H-Ras, K-Ras, N-Ras). In contrast to the extensively studied roles of classical Ras proteins as oncogenes, little is known about molecular and cellular mechanisms for R-Ras. We previously reported that Plexins, the receptors for repulsive guidance molecule semaphorins, functions as a GTPase-activating protein (GAP) for R-Ras and induces direct inactivation of R-Ras. Plexin-mediated R-Ras GAP breaks the positive-feedback loop between R-Ras and integrins, hampering cell adhesiveness and efficiently producing repulsive responses in various cell types, such as collapse and growth inhibition in neuronal growth cones. Ephrins, another member of repulsive guidance factors, also inactivates R-Ras to display repulsive responses. By sharp contrast, attractive guidance factors induce R-Ras activation to exhibit attractive responses. Based on these observations, regulation of R-Ras activity is likely to be a mechanism mutually utilized by a variety of extracellular factors such as attractive and repulsive guidance factors, the extracellular matrix ligands, and growth factors, and R-Ras enables coordinated regulation of various cell functions. In recent years, we have identified several R-Ras-specific effectors responsible for the control of kinase pathways, actin and microtubule cytoskeletons, and intracellular transport. I would like to introduce our recent data, which shed light onto the role of R-Ras as a signaling hub supporting multiple aspects of cellular functions.