A regulatory role for Src homology 2 domain-containing inositol 5′-phosphatase (SHIP) in phagocytosis mediated by Fcγ receptors and complement receptor 3 (αMβ2; CD11b/CD18)

Dianne Cox, B. M. Dale, M. Kashiwada, C. D. Helgason, S. Greenberg

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

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 (FcγRs). 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; αMβ2)-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 FcγR- 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 β2 integrin outside-in signaling.

Original languageEnglish (US)
Pages (from-to)61-71
Number of pages11
JournalJournal of Experimental Medicine
Volume193
Issue number1
DOIs
StatePublished - Jan 1 2001
Externally publishedYes

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Macrophage-1 Antigen
Fc Receptors
Phagocytosis
Macrophages
Phosphatidylinositol 3-Kinase
Inositol Polyphosphate 5-Phosphatases
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Immunoreceptor Tyrosine-Based Inhibition Motif
COS Cells
Cytoskeleton
Integrins

Keywords

  • Actin
  • Integrin
  • Leukocyte
  • Macrophage
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Immunology

Cite this

A regulatory role for Src homology 2 domain-containing inositol 5′-phosphatase (SHIP) in phagocytosis mediated by Fcγ receptors and complement receptor 3 (αMβ2; CD11b/CD18). / Cox, Dianne; Dale, B. M.; Kashiwada, M.; Helgason, C. D.; Greenberg, S.

In: Journal of Experimental Medicine, Vol. 193, No. 1, 01.01.2001, p. 61-71.

Research output: Contribution to journalArticle

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abstract = "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 (FcγRs). 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; αMβ2)-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 FcγR- 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 β2 integrin outside-in signaling.",
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