The Journal of Experimental Medicine
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Published online 27 December 2000.
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© The Rockefeller University Press, 0022-1007/2001/1/61/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 1, January 1, 2001 61-72

Original Article

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}Mß2; CD11b/CD18)

Dianne Coxa, Benjamin M. Dalea, Masaki Kashiwadaa, Cheryl D. Helgasonc, and Steven Greenberga,b
a Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032
b Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York 10032
c Terry Fox Laboratory, Vancouver V52 1L3, British Columbia, Canada

Correspondence to: Steven Greenberg, Columbia University, Departments of Medicine and Pharmacology, 630 West 168th St., New York, NY 10032. Tel:212-305-1586 Fax:212-305-1146 E-mail:greenberg{at}cuccfa.ccc.columbia.edu.

The Src homology 2 domain–containing inositol 5'-phosphatase (SHIP) is recruited to immunoreceptor tyrosine-based inhibition motif (ITIM)–containing proteins, thereby suppressing phosphatidylinositol 3-kinase (PI 3-kinase)–dependent pathways. The role of SHIP in phagocytosis, a PI 3-kinase–dependent pathway, is unknown. Overexpression of SHIP in macrophages led to an inhibition of phagocytosis mediated by receptors for the Fc portion of IgG (Fc{gamma}Rs). In contrast, macrophages expressing catalytically inactive SHIP or lacking SHIP expression demonstrated enhanced phagocytosis. To determine whether SHIP regulates phagocytosis mediated by receptors that are not known to recruit ITIMs, we determined the effect of SHIP expression on complement receptor 3 (CR3; CD11b/CD18; {alpha}Mß2)–dependent phagocytosis. Macrophages overexpressing SHIP demonstrated impaired CR3-mediated phagocytosis, whereas macrophages expressing catalytically inactive SHIP demonstrated enhanced phagocytosis. CR3-mediated phagocytosis in macrophages derived from SHIP-/- mice was up to 2.5 times as efficient as that observed in macrophages derived from littermate controls. SHIP was localized to Fc{gamma}R- and CR3-containing phagocytic cups and was recruited to the cytoskeleton upon clustering of CR3. In a transfected COS cell model of activation-independent CR3-mediated phagocytosis, catalytically active but not inactive SHIP also inhibited phagocytosis. We conclude that PI 3-kinase(s) and SHIP regulate multiple forms of phagocytosis and that endogenous SHIP plays a role in modulating ß2 integrin outside-in signaling.

Key Words: macrophage, integrin, phosphatidylinositol 3-kinase, actin, leukocyte


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