PI3K regulates integrin-dependent processes by signaling through ARAP3, a GTPase activating protein for Arf6 and RhoA

ARAP3 was identified in a screen for phosphatidylinositol-(3,4,5)-trisphosphate (short PIP3) binding proteins from pig leukocyte cytosol as a novel phosphoinositide 3-kinase (PI3K) effector. ARAP3 is a dual GTPase activating protein (GAP) for the small GTPases RhoA and Arf6. Both catalytic activities are regulated by the master regulator, PI3K, with PIP3 causing plasma membrane recruitment of ARAP3. In addition, the small GTPase Rap regulates ARAP3 as a RhoA GAP.

To identify ARAP3’s physiological function, we generated mouse models. Analysis of these models showed that ARAP3 regulates neutrophils, the most common leukocytes in peripheral blood. Our data suggests ARAP3 is required for the correct regulation of neutrophil inside-out signaling, regulating the return of the activated to the basal state. This feeds into many facets of neutrophil biology, one being cell migration (chemotaxis).