A regulatory role for src homology 2 domain-containing inositol 5 '-phosphatase (SHIP) in phagocytosis mediated by Fc gamma receptors and complement receptor 3 (alpha(M)beta(2); CD11b/CD18)

The Src homology 2 domain-containing inositol 5'-phosphatase (SHIP) is recr uited to immunoreceptor tyrosine-based inhibition motif (ITIM)-containing p roteins, thereby suppressing phosphatidylinositol 3-kinase (PI 3-kinase)-de pendent pathways. The role of SHIP in phagocytosis, a PI 3-kinase-dependent pathway, is unknown. Overexpression of SHIP in macrophages led to an inhib ition of phagocytosis mediated by receptors for the Fc portion of IgG (Fc g amma Rs). In contrast, macrophages expressing catalytically inactive SHIP o r lacking SHIP expression demonstrated enhanced phagocytosis. To determine whether SHIP regulates phagocytosis mediated by receptors that are not know n to recruit ITIMs, we determined the effect of SHIP expression on compleme nt receptor 3 (CR3; CD11b/CD18; alpha (M)beta (2))-dependent phagocytosis. Macrophages overexpressing SHIP demonstrated impaired CR3-mediated phagocyt osis, whereas macrophages expressing catalytically inactive SHIP demonstrat ed enhanced phagocytosis. CR3-mediated phagocytosis in macrophages derived from SHIP-/- mice was up to 2.5 times as efficient as that observed in macr ophages derived from littermate controls. SHIP was localized to Fc gammaR- and CR3-containing phagocytic cups and was recruited to thr cytoskeleton up on clustering of CR3. In a transfected COS cell model of activation-indepen dent CR3-mediated phagocytosis, catalytically active but not inactive SHIP also inhibited phagocytosis. We conclude that PI 3-kinase(s) and SHIP regul ate multiple forms of phagocytosis and that endogenous SHIP plays a role in modulating beta (2) integrin outside-in signaling.