Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1

Abstract

Proper neutrophil migration into inflammatory sites ensures host defense without tissue damage. Phosphoinositide 3-kinase (PI(3)K) and its lipid product phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P₃) regulate cell migration, but the role of PtdIns(3,4,5)P₃-degrading enzymes in this process is poorly understood. Here, we show that Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1), a PtdIns(3,4,5)P₃ phosphatase, is a key regulator of neutrophil migration. Genetic inactivation of SHIP1 led to severe defects in neutrophil polarization and motility. In contrast, loss of the PtdIns(3,4,5)P₃ phosphatase PTEN had no impact on neutrophil chemotaxis. To study PtdIns(3,4,5)P₃ metabolism in living primary cells, we generated a novel transgenic mouse (AktPH–GFP Tg) expressing a bioprobe for PtdIns(3,4,5)P_3. Time-lapse footage showed rapid, localized binding of AktPH–GFP to the leading edge membrane of chemotaxing ship1^+/+AktPH–GFP Tg neutrophils, but only diffuse localization in ship1^−/−AktPH–GFP Tg neutrophils. By directing where PtdIns(3,4,5)P₃ accumulates, SHIP1 governs the formation of the leading edge and polarization required for chemotaxis.