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

Abstract

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.

Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease

“…SHIP-1, which is orthologous to INPP5D (inositol polyphosphate-5-phosphatase D) in humans, is found only in hematopoietic cells where it acts as a critical negative regulator of multiple inflammatory signaling pathways (30). We have previously described that SHIP-1-deficient mice spontaneously develop a marked inflammatory lung disease with features reminiscent of clinical COPD, including inflammation, emphysema, and small airway fibrosis (31)(32)(33).…”

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

“…Current data indicate that BCR activates Lyn which phosphorylates the ITIM motif in FcγRIIB, and Grb2 might stabilise SHIP binding to FcγRIIB. Pauls and Marshall [61] presented a model in which BCR stimulation without involvement of FcγRIIB leads to the recruitment of SHIP to the phosphorylated ITAM of BCR dependent on SYK. The SH2 domain of SHIP as well as a complex of proteins including Grb2, Dok-2, and Shc mediate this ITAM recruitment [61].…”

“…The two major SHIP isoforms encoded in mammalian genomes are the 145 kD form SHIP-1 (encoded by the INPP5D gene) and the 142 kD form SHIP-2 (encoded by the INPPL1 gene) [60]. Expression of SHIP-1 is primarily confined to all cells of the haematopoietic lineage such as T, B, and NK cells, granulocytes, platelets, dendritic cells, monocytes/macrophages, and mast cells, but it is also expressed on progenitor and stem cells [12,61]. Through its SH2 domain, SHIP binds to the tyrosine phosphorylated forms of Shc, SHP-2, Dok-3, ITIM receptors like FcγRIIB, CD94, Ly49 and KIR (killer cell immunoglobulin-like receptor), as well as immunoreceptor tyrosine-based activation motif (ITAM) receptors such as FcγRIIA, FcγRI-associated zeta-chain, TCR zeta chain, CD28, FcεRI, and the BCR (Igα/β) [61,62].…”

“…C-terminal to the phosphatase domain, a C2 domain has been identified as an allosteric activating site when bound by PI-3,4-P2. The prolinerich C-terminus of SHIP binds proteins with a phosphotyrosine binding (Dok-1, Dok-2) or an SH2 domain (e.g., SHIP-2) and can also bind SH3-containing proteins such as Grb2, Src, Lyn, Abl, and PLCγ-1 when phosphorylated [61,62]. SHIP-1 functions as a negative regulator in immunoreceptor signaling and haematopoietic progenitor cell proliferation/survival, and as an inducer of cellular apoptosis.…”

“…The best characterised one is the serine/threonine kinase AKT which has a huge range of substrates involved in survival, proliferation, and metabolism. The others are the tyrosine kinase BTK, involved in Ca 2+ signaling with effects on MAPK and NFκB via the BTK/PLCγ signalosome, Rac/ERK via Bam32, involved in proliferation and cytoskeleton regulation, and Vav, also involved in regulation of the cytoskeleton [60,61] (Fig. 4).…”