Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target
Open accessAbstract
The phosphoinositide phosphatase SHIP is a critical regulator of immune cell activation. Despite considerable study, the mechanisms controlling SHIP activity to ensure balanced cell activation remain incompletely understood. SHIP dampens BCR signaling in part through its association with the inhibitory coreceptor Fc gamma receptor IIB, and serves as an effector for other inhibitory receptors in various immune cell types. The established paradigm emphasizes SHIP's inhibitory receptor‐dependent function in regulating phosphoinositide 3‐kinase signaling by dephosphorylating the phosphoinositide PI(3,4,5)P 3 ; however, substantial evidence indicates that SHIP can be activated independently of inhibitory receptors and can function as an intrinsic brake on activation signaling. Here, we integrate historical and recent reports addressing the regulation and function of SHIP in immune cells, which together indicate that SHIP acts as a multifunctional protein controlled by multiple regulatory inputs, and influences downstream signaling via both phosphatase‐dependent and ‐independent means. We further summarize accumulated evidence regarding the functions of SHIP in B cells, T cells, NK cells, dendritic cells, mast cells, and macrophages, and data suggesting defective expression or activity of SHIP in autoimmune and malignant disorders. Lastly, we discuss the biological activities, therapeutic promise, and limitations of small molecule modulators of SHIP enzymatic activity.
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In mouse macrophages, overexpression of SHIP1 inhibits LPS-induced TLR4 signaling and subsequent production of TNF-α and IL-6 by negatively regulating the interaction between TLR4 and MyD88.
“In mouse macrophages, the overexpression of SHIP1 was found to inhibit the LPS-induced TLR4 signaling and the subsequent production of the pro-inflammatory cytokines TNF-α and IL-6 by negatively regulating the interaction between TLR4 and MyD88, though whether this regulation is dependent on SHIP1’s phosphatase activity remains unclear [121, 128]”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [128]
The “Control of MAPK and NFκB pathways” section reports that SHIP overexpression in Raw264.7 macrophages inhibited LPS-induced MAPK activation and TNF-α production and was associated with reduced TLR4–MyD88 interaction. It does not report reduced IL-6 production in those macrophages, and it describes the mechanism linking SHIP to the reduced interaction as unclear rather than established. No page number is available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSHIP1 has emerged as a key negative regulator of inflammation across multiple myeloid and lymphoid signaling pathways.
“Through the integration of its enzymatic and scaffolding functions, SHIP1 has emerged as a key negative regulator of inflammation across multiple myeloid and lymphoid signaling pathways2.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [2]
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Kalidass, B., Murugesan, K., Shanmugam, A., Kaveri, P. K., & Lakshmanan, D. K. (2026) · Cellular Immunology · doi:10.1016/j.cellimm.2026.105129
- Authors
- Pauls, S. D., & Marshall, A. J.
- Affiliations
- University of Manitoba (CA)
- Corresponding author
- Marshall, Aaron J.
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2017-05-26
- Volume
- 47
- Issue
- 6
- Pages
- 932-945
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W2612733314
- Cited by
- 118
- References
- 11
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 9 · 2023: 25 · 2022: 14 · 2021: 9 · 2020: 16 · 2019: 11 · 2018: 12
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP‐93771)
- Institute of Infection and Immunity (MOP‐93771)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- SHIP1, phosphoinositide phosphatase, immune cell signaling, B cell receptor signaling, Fc gamma receptor IIb, inhibitory receptors, phosphoinositide 3-kinase signaling, B cells, T cells, natural killer cells, dendritic cells, mast cells, macrophages, autoimmunity, cancer, therapeutic target
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, B-Lymphocytes, Dendritic Cells, Gene Expression Regulation, Homeostasis, Humans, Killer Cells, Natural, Macrophages, Mast Cells, Phosphorylation, Proteins, T-Lymphocytes, Signal Transduction, Phosphatidylinositol 3-Kinases, Mice
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