Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

SHIP

  • Matthew D. Blunt
  • Stephen G. Ward
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_271

Synonyms

Historical Background

SH2 domain-containing inositol phosphatase-1 (SHIP) was initially identified in 1994 as a tyrosine-phosphorylated protein after stimulation of blood cells by a broad number of cytokines and growth factors (Lioubin et al. 1994; Liu et al. 1994). It translocates to the plasma membrane after extracellular stimulation and hydrolyses the  phosphoinositide 3-kinase (PI3K)-generated second messenger PI(3,4, 5)P3, to PI(3,4)P2. As a result, SHIP is able to modulate PI(3,4,5)P3-mediated signaling and hence the proliferation, differentiation, survival, activation, and migration of hematopoietic cells. The creation of germ-line SHIP–/– knockout mice in 1998 was instrumental in determining the role SHIP plays in the immune system (Helgason et al. 1998). Subsequent cell-restricted deletion in lymphoid and myeloid compartments some 10 years later, further advanced understanding of the intrinsic role of SHIP in a variety of immune cells (Leung et al. 2009).

Structure and Binding Partners of SHIP Family Members

SHIP is a 145 kDa protein encoded by the INPP5D gene on chromosome 2 (location 2q37.1) and is largely confined to hematopoietic cells. The protein is composed of 1188 amino acids and possesses domains that mediate its interaction with other proteins on either side of its central catalytic domain. In addition to hydrolysing PI(3,4,5)P3, SHIP can also dephosphorylate inositol-1,3,4,5-tetraphosphate, at least in vitro. SHIP possesses a centrally located catalytic domain responsible for the hydrolysis of the 5′-phosphate of the membrane phosphoinositide lipid PI(3,4, 5)P3, the major product of receptor-activated PI3K. A C2 domain adjacent to the catalytic domain has been identified and shown to be an allosteric- activating site when bound by SHIP’s enzymatic product PI(3,4)P2 (Hamilton et al. 2011). In addition, SHIP encodes multiple structural domains that facilitate protein–protein interactions and cellular re-localization upon receptor stimulation. The SH2 domain within SHIP interacts with proteins via the consensus amino acid sequence pY[S/Y][L/Y/M][L/M/I/V]. Through this SH2 domain, SHIP binds to the tyrosine phosphorylated forms of Shc, Doks, Gabs, CD150, platelet-endothelial cell adhesion molecule (PECAM), Cas, c-Cbl certain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and some immunoreceptor tyrosine-based activation motifs (ITAMs). Recruitment of SHIP by the phosphorylated ITIM in the cytoplasmic domain of FcRIIB was shown to inhibit recruitment of PH-domain-containing proteins and prevent extracellular calcium influx, overall reducing transcription activation, and cytokine release. The proline-rich region of SHIP enables interaction with proteins encoding SH3 domains, such as Grb2, Src, Lyn and phospholipase-C? and is essential for SHIP function (Harris et al. 2008). The two NPXY motifs in SHIP can become tyrosine phosphorylated and bind the phosphotyrosine-binding domain (PTB) motifs in Shc, Dok1, and Dok 2. These structural domains of SHIP are able to support the re-localization of SHIP from the cytosol to the plasma membrane, where its catalytic activity regulates PI(3,4,5)P3 accumulation. In addition, these structural features and binding motifs allow SHIP to serve a scaffolding role for the recruitment of other proteins to the plasma membrane, independent of catalytic function. The interaction of SHIP with other proteins can also indirectly abrogate PI3K signaling since SH2 domain-mediated interactions with ITAM-containing adaptor proteins has been demonstrated to dislodge or prevent further recruitment of PI3K via the p85 subunit (Peng et al. 2010).

Splice Variants and Isoforms of SHIP

Multiple forms of SHIP have been reported with molecular weights of 145 (SHIPα),135 (SHIPß), and 110 (SHIPδ) kDa (Fig. 1). In addition, other 130, 125, and 110 kDa forms of SHIP have been reported (Hamilton et al. 2011; Kerr 2011). The different forms of SHIP may arise from alternative mRNA splicing, protein degradation, or posttranslational modification such as phosphorylation. SHIP-2 is a 142 kDa protein that is highly homologous with the hematopoietic-specific SHIP, but is encoded by a different gene and exhibits distinct structural features as well as possibly having a broader phospholipid substrate specificity than SHIP, as it also hydrolyses PI(4,5)P2 in vitro. SHIP-2 is expressed in both hematopoietic and non-hematopoietic tissues such as brain, skeletal muscle, heart, and to a lesser extent liver and kidney. The major role of SHIP-2 appears to be the negative regulation of insulin signaling in nonimmune cells (Ooms et al. 2009).
SHIP, Fig. 1

Schematic representation of the SHIP protein isoforms. The protein interaction motifs are indicated, along with their binding partners. The SH2 domain allows SHIP to bind proteins (such as those indicated) which express the sequence phospho-Y(Y/S/T)L(M/L). The 5′ phosphatase domain catalyzes the conversion of PI(3,4,5)P3 to PI(3,4)P2. The C2 domain has been identified as a binding domain of the SHIP product PI(3,4)P2 which acts to increase the catalytic activity of SHIP. The NPXY motifs when phosphorylated provide binding sites for proteins which express phosphotyrosine binding domains. The proline-rich domain (PR) allows SHIP to interact with SH3 domain-containing proteins

The different forms of SHIP exhibit different protein-binding profiles defined by the absence or presence of these distinct binding motifs that are described in more detail below (Fig. 1). For example, s-SHIP (expression of which is restricted to murine embryonic stem cells and primitive hematopoietic stem cells, but which is lost in lineage-committed hematopoietic cells) and its human homologue SIP-110, are truncated at the N-terminus and lack the SH2 domain which limits the repertoire of binding proteins available for interaction. For example, it cannot interact with Shc, but still interacts with Grb-2. Moreover, s-SHIP is mostly localized at the plasma membrane rather than the cytoplasm (Hamilton et al. 2011; Kerr 2011).

SHIP: A Checkpoint in PI3K-Dependent Signaling

The classical view of SHIP is that it acts to switch off PI3K-dependent signaling by degradation of PI(3,4,5)P3 (Fig. 2). However, the metabolism of PI(3,4,5)P3 by SHIP yields PI(3,4)P2 which retains the phosphate grouping on the third position of the inositol ring and thus, may retain some signaling ability. Pleckstrin homology (PH) domains encoded in many proteins (e.g., Grp-1) bind exclusively to PI(3,4,5)P3, whereas others such as that found in dual adaptor of phosphotyrosine and 3-phosphoinositides -1 (DAPP-1), can interact with both PI(3,4,5)P3 and PI(3,4)P2 (Lemmon and Ferguson 2000). In addition, the tandem PH domain-containing protein TAPP-1 encodes PH domains that show selectivity toward PI(3,4)P2 (Harris et al. 2008). The ability of PH domain-containing proteins to distinguish between different 3′-phosphoinositide lipids suggests that SHIP can act as a switch to redirect PI3K-dependent signaling toward a set of distinct effectors that are temporally and functionally separate from PI(3,4,5)P3-dependent events. Thus, SHIP may function to fine-tune phosphoinositide signaling, rather than terminate it (Fig. 2). In this regard, SHIP promotes recruitment of the GTPase Irgm1 to sites of phagocytosis in macrophages via generation of PI(3,4)P2, a critical step in maturation of the phagosome and engulfment of bacteria. PI(3,4,5)P3 and PI(3,4)P2 appear sequentially following agonist stimulation in many cell types including T lymphocytes, but show temporal overlap. Some cell types, notably B lymphocytes and platelets, exhibit sustained PI(3,4)P2 production, lasting for up to 45–60 min poststimulation (Harris et al. 2008).
SHIP, Fig. 2

SHIP acts as a molecular “switch”. SHIP catalyzes the conversion of the PI3K lipid product PI(3,4,5)P3 to PI(3,4)P2. Effector proteins which express PH domains are recruited and activated by these lipid second messengers at the cell surface membrane. PH-domains of proteins are able to discriminate between PI(3,4,5)P3 and PI(3,4)P2. Examples of proteins which bind only PI(3,4,5)P3, both PI(3,4,5)P3 and PI(3,4)P2 or only PI(3,4)P2 are shown (a). This diversity allows SHIP to both negatively regulate PI3K signaling and also to “switch” signal transduction pathways away from PI(3,4,5)P3-dependent effectors toward PI(3,4)P2-dependent effectors, in turn influencing kinetics and duration of recruitment of 3’ phosphoinositide lipid binding proteins at the plasma membrane (depicted in b)

Role of SHIP in the Immune System: Maintaining a Balance Between Inflammatory and Regulatory Cells

SHIP is expressed ubiquitously in differentiated cells of the hematopoietic system, in endothelial cells, hematopoietic stem cells (HSC), and embryonic stem (ES) cells. Both SHIP and s-SHIP have been implicated in the biology of pluripotent and adult stem cells. More recently, it has been shown to play a key role in the function of the bone marrow microenvironment (the stem cell niche) (Kerr 2008). Largely as a consequence of hematopoietic-specific expression, SHIP has been extensively studied for its regulatory role in B cells, T cells, macrophages and mast cells. SHIP was first recognized as an important component of the inhibitory signaling pathway triggered by the IgG receptor Fc?RIIB in mast cells and B cells (Ono et al. 1996). Once recruited to the plasma membrane by signaling complexes, its catalytic activity depletes PI(3,4,5)P3 and prevents membrane localization of some PH domain-containing effectors. SHIP has also been implicated in signaling pathways triggered by cytokine, chemokine, antigen, and IgG engagement in a variety of immune cells (Harris et al. 2008). Additionally, SHIP plays an important regulatory role in establishing endotoxin tolerance in macrophages as well as regulating leucocyte polarization during migratory responses to chemoattractants (Hamilton et al. 2011; Harris et al. 2008; Kerr 2011).

Genetic analysis of SHIP mutant mice has revealed a pivotal role for SHIP in a wide variety of differentiated hematopoietic cell types. SHIP has been shown to play a role in regulating the receptor repertoire and cytolytic function of Natural Killer (NK) cells, B lymphocyte development and antibody production, the myeloid cell response to bacterial mitogens, development of marginal zone macrophages, lymph node recruitment of dendritic cells, and mast cell degranulation (Fig. 3). The negative regulatory role for SHIP in the immune system is best illustrated by the phenotype of SHIP null mice which develop progressive myeloid hyperplasia and myeloid infiltration in the lungs that leads to respiratory failure and to a dramatic decrease of life span. The myeloid hyper-proliferation is caused by the combination of two factors. First, the myeloid cells and their precursors are more sensitive to growth factors and second, these cells show a decreased sensitivity to pro-apoptotic stimuli (Helgason et al. 1998). Analysis of the SHIP null mice has also established that SHIP plays a critical role in homeostasis of myleoid and lymphoid effector and regulatory cells. For example, SHIP deficient mice exhibit more myeloid-derived suppresser cells (MDSCs) than their wild type counterparts. SHIP also plays a role in regulating the balance of M1 macrophages (implicated in the first inflammatory response) and M2 macrophages (implicated in inflammatory response termination, tissue repair, regeneration and remodeling). SHIP deficiency leads to increased macrophage skewing toward M2 macrophages. This indicates that PI(3,4,5)P3 drives macrophage progenitors toward an M2 phenoype and that SHIP blocks this skewing (Hamilton et al. 2011; Kerr 2011). Moreover, SHIP is essential for normal Th17 cell development and this lipid phosphatase plays a key role in the reciprocal regulation of Tregs and Th17 cells (Hamilton et al. 2011; Kerr 2011). Because of abnormalities in secretion of cytokines observed in SHIP-deficient mice, the root cause of an abnormality in SHIP-deficient mice could also be due to extrinsic effects on that cell type. Thus, analysis of cell type specific deletion of SHIP in vivo is ultimately required before one can conclusively determine which SHIP-deficient cell type causes a specific phenotype in mice with a germline homozygous mutation of SHIP. This is best illustrated by analysis of mice carrying a T cell-specific deletion of SHIP, which uncovered a regulatory role for SHIP in controlling Th1/Th2 bias and cytotoxic responses as a result of its inhibitory effect on T-bet expression. Mice with a T cell-specific deletion of SHIP revealed that they do not skew efficiently to a Th2 phenotype and display Th1-dominant immune responses in vitro and in vivo (Leung et al. 2009). This is in contrast to evidence from germ line SHIP-/- mice, which indicates that SHIP can also repress Th2 skewing by inhibiting IL-4 production from basophils (Hamilton et al. 2011).
SHIP, Fig. 3

SHIP regulates immune cell functions and influences tumor development and growth. SHIP plays a key role in the generation of lymphocyte and myeloid subsets and maintaining a balance between inflammatory and regulatory cells. Thus, modulation of SHIP offers potential for therapeutic intervention in a range of inflammatory and autoimmune diseases as well as in cancer and transplantation settings

SHIP in Cancer and Other Diseases: Opportunities for New Therapies

The PI3K-dependent signaling pathway has a well-established role in regulating cell survival, proliferation and differentiation (Manning and Cantley 2007). As such, the levels of PI(3,4,5)P3 are tightly regulated not only by SHIP but also by the 3’ lipid phosphatase  PTEN (Harris et al. 2008). The importance of these lipid phosphatases is underlined by the fact that PTEN is frequently lost in many leukemias and immortalized leukemic cell lines (Hollander et al. 2011). SHIP expression is also frequently lost, downregulated, or mutated in many cancer cells including acute myeloid leukemia (AML). MicroRNAs (miRNAs) are recently discovered regulators of gene expression that have a role in the regulation of hematopoiesis, the immune response and inflammation. MicroRNAs can repress protein expression through their ability to bind directly to the 3′UTRs of specific genes and prevent translation of the protein products. Scanning of the SHIP 3′ UTR revealed perfect sequence complementarity with the seed sequence of miR-155. Elevated levels of miR-155 and consequent diminished SHIP expression have been linked to B cell lymphomas (Costinean et al. 2009). In addition, it has been reported that oncogenic proteins including BCR/Abl, and Tax (implicated in chronic myelogenous leukemia and adult T cell leukemia/lymphoma, respectively), induce SHIP downregulation by a variety of mechanisms (Kerr 2011). Consistent with its role as a tumor suppressor, SHIP restricts development of MDSCs and Tregs. Thus, SHIP deficiency leads to an expansion of MDSCs and Tregs and hence, suppression of T cell immune responses and so, this may be another mechanism for increased tumorigenesis if SHIP expression is reduced. However, the role of SHIP in leukemia seems more complex than initially thought, since there is evidence that SHIP can actually support cancer cell survival as a small molecule inhibitor of SHIP induces apoptosis of multiple myeloma cells (Brooks et al. 2010). This is consistent with its production of PI(3,4)P2 which is known to facilitate Akt activation and hence cell proliferation, survival, and tumorigenesis (Manning and Cantley 2007). Others have shown that SHIP inhibits CD95/APO-1/Fas-induced apoptosis in T cells by promoting CD95 glycosylation independently of its phosphatase activity (Charlier et al. 2010).

HSC proliferation and numbers are increased in SHIP–/– mice. Despite expansion of the compartment, SHIP deficient HSCs exhibit reduced capacity for long-term repopulation and home inefficiently to bone marrow. The role of SHIP in the biology of both HSC and the hematopoietic stem cell niche, suggests that it may be a useful target for treatment of bone marrow failure syndromes caused by viruses, radiation, chemotherapy, or malignancy. As already mentioned, MDSCs are a type of immunoregulatory cell that can repress allogeneic T cell responses. A common complication arising after bone marrow transplantation is Graft-versus-host disease (GVHD) which involves priming of allogeneic T cells. Remarkably, SHIP deficient mice express more myeloid suppressor cells than their WT counterparts and accept allogeneic bone marrow grafts with a reduced incidence of GVHD (Ghansah et al. 2004; Kerr 2008).

The key regulatory role of SHIP has been exploited by several opportunistic pathogens that target these phosphatases in order to evade immune detection. Thus, lymphocytes are particularly sensitive to the cytolethal distending toxin subunit B (CdtB), an immunotoxin produced by Actinobacillus actinomycetemcomitans that can hydrolyse PI(3,4,5)P3 to PI(3,4)P2. Exposure to CdtB leads to cell cycle arrest and death by apoptosis. The lipid phosphatase activity of CdtB may therefore result in reduced immune function, facilitating chronic infection with Actinobacillus and other enteropathogens that express Cdt proteins (Shenker et al. 2007). The measles virus evades destruction by the immune system at least in part, by targeting negative regulation of PI3K/Akt signaling. It induces expression of SIP-110 which depletes the cellular PI(3,4,5)P3 pools, suggesting that the threshold for activation signals leading to induction of T cell proliferation is raised (Avota et al. 2006).

The role of SHIP in regulating the development and function of various hematopoietic cells and evidence linking SHIP to cancer and other diseases, has led to the search for small molecules that are able to modulate activity and which may be useful as drugs. Several compounds have now been reported and have been shown to exert an anti-inflammatory effect in in vitro and in vivo models (Harris et al. 2008). Moreover, these molecules have been sucessfully used to kill multiple myeloma cells in vitro indicating that SHIP agonists could be effective anticancer agents. Small molecule inhibitors of SHIP have also been reported which, consistent with observations from SHIP deleted mice, led to increased myeloid suppressor cells, reduced ability of peripheral lymphoid tissues to prime myeloid-associated responses, and protected against GVHD. SHIP inhibitors increased levels of granulocytes, red blood cells, neutrophils, and platelets in mice and could therefore, have application to improve blood cell number in patients with myelodysplastic syndrome or myelosuppressive infection. A SHIP inhibitor also triggered the apoptosis of human acute myeloid leukemia cell lines, consistent with SHIP being anti-apoptotic under some circumstances (Brooks et al. 2010).

Summary

SHIP is largely confined to hematopoietic cells and modulates PI3K/Akt dependent signaling by hydrolysing the PI3K-generated second messenger PI(3,4,5)P3, to PI(3,4)P2. As a consequence, SHIP is able to modulate PI(3,4,5)P3-mediated signaling and hence the proliferation, differentiation, survival, activation, and migration of hematopoeitic cells. SHIP possesses a centrally located catalytic domain responsible for the hydrolysis of the 5′-phosphate of the membrane phosphoinositide lipid PI(3,4,5)P3. In addition, SHIP possesses multiple structural domains that facilitate protein–protein interactions and cellular re-localization upon receptor stimulation. These structural features and binding motifs allow SHIP to serve a scaffolding role for the recruitment of other proteins to the plasma membrane. Indeed, SHIP has been shown to exert several functional effects independently of its catalytic function. The ability of PH domain-containing proteins to distinguish between different 3′-phosphoinositide lipids suggests that SHIP can act as a switch to redirect PI3K signaling toward PI(3,4)P2-dependent effectors that are temporally and functionally separate from PI(3,4,5)P3-dependent events. Thus, SHIP may function to fine-tune phosphoinositide signaling, rather than terminate it. SHIP can regulate a variety of signaling pathways related to cytokine, chemokine, antigen, and IgG engagement in both lymphocytes and myeloid cells. It plays a key role in the generation of lymphocyte and myeloid subsets and maintaining a balance between inflammatory and regulatory cells. Additionally, SHIP plays an important regulatory role in establishing endotoxin tolerance in macrophages, as well as regulating leucocyte polarization during migratory responses to chemoattractants. The expression of SHIP and/or its activity is often targeted by pathogens, whilst SHIP expression is lost, downregulated or mutated in many cancer cells. Thus, modulation of SHIP offers potential for therapeutic intervention in a range of inflammatory and autoimmune diseases as well as in cancer and transplantation settings.

References

  1. Avota E, Harms H, Schneider-Schaulies S. Measles virus induces expression of SIP110, a constitutively membrane clustered lipid phosphatase, which inhibits T cell proliferation. Cell Microbiol. 2006;8:1826–39.PubMedCrossRefGoogle Scholar
  2. Brooks R, Fuhler GM, Iyer S, Smith MJ, Park MY, Paraiso KH, Engelman RW, Kerr WG. SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells. J Immunol. 2010;184:3582–9.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Charlier E, Conde C, Zhang J, Deneubourg L, Di Valentin E, Rahmouni S, Chariot A, Agostinis P, Pang PC, Haslam SM, Dell A, Penninger J, Erneux C, Piette J, Gloire G. SHIP-1 inhibits CD95/APO-1/Fas-induced apoptosis in primary T lymphocytes and T leukemic cells by promoting CD95 glycosylation independently of its phosphatase activity. Leukemia. 2010;24:821–32.PubMedCrossRefGoogle Scholar
  4. Costinean S, Sandhu SK, Pedersen IM, Tili E, Trotta R, Perrotti D, Ciarlariello D, Neviani P, Harb J, Kauffman LR, Shidham A, Croce CM. Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein-beta are targeted by miR-155 in B cells of E{micro}-MiR-155 transgenic mice. Blood. 2009;114:1374–82.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Ghansah T, Paraiso KHT, Highfill S, Desponts C, May S, McIntosh JK, Wang J-W, Ninos J, Brayer J, Cheng F, Sotomayor E, Kerr WG. Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses. J Immunol. 2004;173:7324–30.PubMedCrossRefGoogle Scholar
  6. Hamilton MJ, Ho VW, Kuroda E, Ruschmann J, Antignano F, Lam V, Krystal G. Role of SHIP in cancer. Exp Hematol. 2011;39:2–13.PubMedCrossRefGoogle Scholar
  7. Harris SJ, Parry RV, Westwick J, Ward SG. Phosphoinositide lipid phosphatases: natural regulators of phosphoinositide 3-kinase signaling in T lymphocytes. J Biol Chem. 2008;283:2465–9.PubMedCrossRefGoogle Scholar
  8. Helgason CD, Damen JE, Rosten P, Grewal R, Sorensen P, Chappel SM, Borowski A, Jirik F, Krystal G, Humphries RK. Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev. 1998;12:1610–20.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011;11:289–301.PubMedCrossRefGoogle Scholar
  10. Kerr WGA. Role for SHIP in stem cell biology and transplantation. Curr Stem Cell Res Ther. 2008;3:99–106.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Kerr WG. Inhibitor and activator: dual functions for SHIP in immunity and cancer. Ann N Y Acad Sci. 2011;1217:1–17.PubMedCrossRefGoogle Scholar
  12. Lemmon MA, Ferguson KM. Signal-dependent membrane targeting by pleckstrin homology (PH) domains. Biochem J. 2000;350:1–18.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Leung WH, Tarasenko T, Bolland S. Differential roles for the inositol phosphatase SHIP in the regulation of macrophages and lymphocytes. Immunol Res. 2009;43:243–51.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Lioubin MN, Myles GM, Carlberg K, Bowtell D, Rohrschneider LR. Shc, Grb2, Sos1, and a 150-kilodalton tyrosine-phosphorylated protein form complexes with Fms in hematopoietic cells. Mol Cell Biol. 1994;14:5682–91.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Liu L, Damen JE, Cutler RL, Krystal G. Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc. Mol Cell Biol. 1994;14:6926–35.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Ono M, Bolland S, Tempst P, Ravetch JV. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc?RIIB. Nature. 1996;383:263–6.PubMedCrossRefGoogle Scholar
  18. Ooms LM, Horan KA, Rahman P, Seaton G, Gurung R, Kethesparan DS, Mitchell CA. The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J. 2009;419:29–49.PubMedCrossRefGoogle Scholar
  19. Peng Q, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal. 2010;3:ra38.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Shenker BJ, Dlakic M, Walker LP, Besack D, Jaffe E, LaBelle E, Boesze-Battaglia K. A novel mode of action for a microbial-derived immunotoxin: the cytolethal distending toxin subunit B exhibits phosphatidylinositol 3,4,5-triphosphate phosphatase activity. J Immunol. 2007;178:5099–108.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Matthew D. Blunt
    • 1
  • Stephen G. Ward
    • 2
  1. 1.Department of Pharmacy and PharmacologyUniversity of BathBathUK
  2. 2.Department of Pharmacy and PharmacologyUniversity of Bath, Claverton DownBathUK