Phosphoinositide lipid phosphatase SHIP1 and PTEN coordinate to regulate cell migration and adhesion

Abstract

The second messenger phosphatidylinositol(3,4,5)P₃ (PtdIns(3,4,5)P₃) 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)P₃ 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)P₃ compass. In this study, we show that SHIP1 regulates PtdIns(3,4,5)P₃ 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)P₃ production. From our observations, we conclude that SHIP1 prevents formation of top-down PtdIns(3,4,5)P₃ polarity to facilitate proper cell attachment and detachment during chemotaxis.}