Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

• Published in: European journal of immunology 2017-06, Vol.47 (6), p.932-945
• Main Authors: Pauls, Samantha D., Marshall, Aaron J.
• Format: Article
• Language: English
• Subjects: Activation analysis; Animals; B-Lymphocytes - enzymology; B-Lymphocytes - immunology; Brakes; Cell activation; Cellular activation; Dendritic cells; Dendritic Cells - enzymology; Dendritic Cells - immunology; Enzymatic activity; Fc receptors; Gene Expression Regulation; Homeostasis; Humans; Inhibitory receptors; Inositol-1,4,5-trisphosphate 5-phosphatase; Killer Cells, Natural - enzymology; Killer Cells, Natural - immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; Macrophages; Macrophages - enzymology; Macrophages - immunology; Mast cells; Mast Cells - enzymology; Mast Cells - immunology; Mice; Phosphatase; Phosphatidylinositol 3,4,5-triphosphate; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - chemistry; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - genetics; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - metabolism; Phosphorylation; Proteins - metabolism; Protein–protein interactions; Receptor mechanisms; Ships; Signal transduction; Signal Transduction - genetics; T cell receptors; T-Lymphocytes - enzymology; T-Lymphocytes - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201646795

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)P3; 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. SHIP1 is a multifunctional protein that regulates immune cell activation via PIP3 phosphatase and adaptor/scaffold activities. Accumulated evidence points to multifaceted regulatory functions of SHIP1 in autoimmune/inflammatory diseases and cancer. SHIP1 has recently emerged as a promising therapeutic target