Ras GTPase-activating protein 3 (RASA3)

Ras GTPase-activating protein 3 (RASA3) is an intracellular enzyme that negatively regulates the Ras signaling pathway by catalyzing the hydrolysis of GTP bound to Ras, turning it into the inactive GDP-bound form. This process suppresses cell proliferation and influences differentiation in multiple blood cell lineages, especially megakaryocytes and erythrocytes. RASA3 is also the first identified high-affinity inositol 1,3,4,5-tetrakisphosphate receptor. Mutations or mislocalization of RASA3 cause loss of its function, resulting in increased active Ras and downstream signaling abnormalities, including delayed erythroid differentiation and altered integrin signaling. RASA3 interacts with other signaling molecules, such as HCK (a Src family kinase). It has distinct structural domains, including a pleckstrin-homology domain for plasma membrane targeting and high-affinity binding to IP4. Disease implications relate mainly to its regulatory role over Ras, which is a central node in many cancers.

Other names

GAP1(IP4BP) (GTPase Activating Protein III, Inositol 1,3,4,5-tetrakisphosphate receptor)R-Ras GTPase-activating protein

Ras pathway inhibitors generally function by blocking Ras activation or by modulating RasGAP proteins’ action, restoring control over Ras-driven cell proliferation. RASA3 itself acts by accelerating GTP hydrolysis (inactivation) of Ras proteins.