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Cited by 158Phagocytosis and Immune RegulationCellular transport and secretionNeutrophil, Myeloperoxidase and Oxidative Mechanisms

A Regulatory Role for Src Homology 2 Domain–Containing Inositol 5′-Phosphatase (Ship) in Phagocytosis Mediated by Fcγ Receptors and Complement Receptor 3 (α M β 2; Cd11b/Cd18)

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Cox, Dianne, Dale, Benjamin M., Kashiwada, Masaki, Helgason, Cheryl D., Greenberg, Steven·2001·The Journal of Experimental Medicine
DOI 10.1084/jem.193.1.61PMC PMC2195884
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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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  • SHIP1 directly inhibits FCγRIIA by binding to its ITAM, which prevents activation of PI3K.

    “SHIP1 also was shown to directly inhibit FCγRIIA by binding to its ITAM (Fig. 3C), which prevents the activation of PI3K [134, 137–140].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [138]

    The Introduction (page unavailable) reports that SHIP can bind ITAM-bearing peptides from an Fc receptor γ subunit in vitro, while the Discussion says SHIP downmodulates FcγR-mediated phagocytosis. Neither establishes direct binding to FcγRIIA’s ITAM. The Discussion describes SHIP hydrolyzing a PI3K product, PtdIns(3,4,5)P3, rather than preventing PI3K activation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In mouse macrophages and COS cells, SHIP1 activates the ITIM of the inhibitory receptor FCγRIIβ, which inhibits the activating receptor FCγRIIA to block FCγRIIA-mediated phagocytosis.

    “In mouse macrophages and COS cells, SHIP1 was shown to activate the ITIM of the inhibitory receptor FCγRIIβ, which inhibits the activating receptor FCγRIIA to block FCγRIIA-mediated phagocytosis (Fig. 3C).”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [138]

    The Results section, “SHIP Is a Negative Regulator of FcγR-mediated Phagocytosis” (page unavailable), shows that SHIP inhibits FcγR-mediated phagocytosis in macrophages. But the Introduction says SHIP is recruited to an already-phosphorylated FcγRIIB ITIM, not that SHIP activates it. The paper does not establish inhibition of FcγRIIA specifically, and its COS-cell experiments concern CR3-mediated phagocytosis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • SHIP1 modulates CR3-mediated phagocytosis in macrophages.

    “SHIP1 also has been shown to modulate complement receptor 3 (CR3)-mediated phagocytosis in macrophages [134, 138, 141].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [138]

  • Wild-type SHIP1, but not its catalytically inactive form, inhibits phagocytosis of a ligand selective for CR3 in mouse macrophages, suggesting that the phosphatase activity of SHIP1 is required for its inhibition of CR3-mediated phagocytosis.

    “Wild-type SHIP1, but not its catalytically inactive form, was found to inhibit the phagocytosis of a ligand selective for CR3 in mouse macrophages, suggesting that the phosphatase activity of SHIP1 is required for its inhibition of CR3-mediated phagocytosis [138] (Fig. 3C).”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [138]

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Authors
Cox, D., Dale, B. M., Kashiwada, M., Helgason, C. D., & Greenberg, S.
Affiliations
  • Columbia University (US)
  • Terry Fox Research Institute (CA)
  • Columbia University Irving Medical Center (US)
ORCID
Cox, Dianne
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2000-12-27
Volume
193
Issue
1
Pages
61-72
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.193.1.61
PMC
PMC2195884
OpenAlex
W2106994186
Cited by
158
References
4
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2021: 6 · 2020: 7 · 2019: 1 · 2018: 3 · 2017: 6 · 2016: 3 · 2015: 5 · 2014: 1 · 2013: 4 · 2012: 8
FWCI
3.66
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL054164, HL 54164)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR02158, K01AR002158)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
ships, inositol polyphosphate 5-phosphatase, phagocytosis, complement receptor 3, CD11b/CD18, Fc gamma receptor, macrophages, phosphatidylinositol 3-kinase, ITIM, phagocytic cup
MeSH terms
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, Cells, Cultured, Cytoskeleton, Phagocytosis, Phagosomes, Phosphoric Monoester Hydrolases, Transfection, Macrophage-1 Antigen, Receptors, IgG, Mice, Knockout, src Homology Domains, COS Cells, Phosphatidylinositol 3-Kinases, Mice

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