Ras-Gefs and Ras Gaps

Abstract

Ras proteins (H-, N-, and K-Ras) are critical components of signal transduction pathways leading from cell-surface receptors to the control of cell proliferation, differentiation or death. Normal Ras proteins exist in equilibrium between an active (Ras-GTP) and an inactive (Ras-GDP) state. Once activated, Ras stimulates a multitude of downstream signaling pathways, but different data about Ras location to plasma membrane subdomains and new roles for some docking/scaffold proteins, point to signaling specificities of the different Ras proteins. Studies with knockout mice strains have revealed that Kras (but not Nras or Hras) is necessary and sufficient for development of the animals to the adult stage. Although Ras proteins possess intrinsic GTPase and GDP/GTP exchange activities, they are too low to account for the rapid and transient GDP/GTP cycling that occurs during mitogenic stimulation. Then, Ras function requires regulatory proteins that control the GDP/GTP cycling rate. These regulatory proteins include GTPase activating proteins (Ras-GAPs), which stimulate hydrolysis of bound GTP to GDP, and guanine nucleotide exchange factor proteins (Ras-GEFs), which promote the replacement of bound GDP with GTP. We undertook this review to analyze the current understanding of the mammalian Ras-GAPs and Ras-GEFs functions, focusing on the possible physiological specificities of each Ras-GAP/Ras-GEF family member. Furthermore, we analyzed new mechanisms of Rac activation due to covalent-interaction with hydrophobic molecules as NO and cyclopentenone prostaglandins