Phosphoinositide Lipid Posphatase SHIP1 and PTEN Coordinate to Regulate Cell Migration and Adhesion

Abstract

The second messenger phosphatidylinositol$(3,4,5)P_3 (PtdIns(3,4,5)P_3)$ is formed by stimulation of various receptors, including G protein–coupled receptors and integrins. The lipid phosphatases PTEN and SHIP1 are critical in regulating the level of PtdIns$(3,4,5)P_3$ during chemotaxis. Observations that loss of PTEN had minor and loss of SHIP1 resulted in a severe chemotaxis defect in neutrophils led to the belief that SHIP1 rather than PTEN acts as a predominant phospholipid phosphatase in establishing a PtdIns$(3,4,5)P_3$ compass. In this study, we show that SHIP1 regulates PtdIns$(3,4,5)P_3$ production in response to cell adhesion and plays a limited role when cells are in suspension. $SHIP1^{−/−}$ neutrophils lose their polarity upon cell adhesion and are extremely adherent, which impairs chemotaxis. However, chemo­taxis can be restored by reducing adhesion. Loss of SHIP1 elevates Akt activation following cell adhesion due to increased PtdIns$(3,4,5)P_3$ production. From our observations, we conclude that SHIP1 prevents formation of top-down PtdIns$(3,4,5)P_3$ polarity to facilitate proper cell attachment and detachment during chemotaxis