Mini-reviewA thirty-year quest for a role of R-Ras in cancer: from an oncogene to a multitasking GTPase

- A historic prospective of the identification and initial characterization of R-Ras as a Ras-related oncogene.
- A description of the spectrum of integrin receptors being activated by R-Ras and the underlying mechanisms involved.
- An overview of the role of semaphorin/plexin signaling in cell-cell communication through regulating the activation states of R-Ras.
- A summary of the phenotypes being reported in R-Ras knockout mouse lines.
- A review of the roles of R-Ras in human cancer and its potential role in the tumor microenvironment .

Since the identification of R-Ras, which is the first Ras-related GTPase isolated based on sequence similarity to the classical RAS oncogene, more than 160 members of the Ras superfamily of GTPases have been identified and classified into the Ras, Rho, Rap, Rab, Ran, Arf, Rheb, RGK, Rad, Rit, and Miro subfamilies. R-Ras belongs to the Ras subfamily of small G-proteins, which are frequently implicated in cell growth and differentiation. Although the roles of R-Ras in cellular transformation and integrin-mediated cell adhesion have been extensively studied, the physiological function of this enigmatic G-protein was only revealed when a mouse strain deficient in R-Ras was generated. In parallel, a plethora of research findings also linked R-Ras with processes including tumor angiogenesis, axon guidance, and immune cell trafficking. Several upstream factors that modulate R-Ras GTP-binding were identified including Notch, semaphorin, and chemokine C-C motif ligand 21. A review of our evolving understanding of the role of R-Ras in oncogenesis is timely, as this year marks the 30th anniversary of the publication describing the cloning of R-Ras.