The Role of R-Ras Proteins in Normal and Pathologic Migration and Morphologic Change

The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome (NS), a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular, and nervous systems. Consistent with the abnormalities seen in NS, a host of new studies have implicated R-Ras proteins in physiological and pathologic changes in cellular morphology, adhesion, and migration in the cardiovascular, immune, and nervous systems. These changes include regulating the migration and homing of mature and immature immune cells, vascular stabilization, clotting, and axonal and dendritic outgrowth during nervous system development. Dysregulated R-Ras signaling has also been linked to the pathogenesis of cardiovascular disease, intellectual disabilities, and human cancers. This review discusses the structure and regulation of R-Ras proteins and our current understanding of the signaling pathways that they regulate. It explores the phenotype of NS patients and their implications for the R-Ras subfamily functions. Next, it covers recent discoveries regarding physiological and pathologic R-Ras functions in key organ systems. Finally, it discusses how R-Ras signaling is dysregulated in cancers and mechanisms by which this may promote neoplasia.