Disease relevance of Inpp5d

• Indeed Lyn-deficient mice are hyper-responsive to myeloid growth factors and develop a myeloproliferative disorder that predisposes the mice to macrophage tumours, with loss of negative regulation through SHP-1 and SHIP-1 thought to be the major contributing factor to this phenotype [1].
• Accordingly, SHIP1-null mice showed defects in arterial thrombus formation in response to a localized laser-induced injury [2].

High impact information on Inpp5d

• In this report, we demonstrate that the Src homology 2 domain-containing inositol-5-phosphatase (SHIP) plays a critical role in regulating both B cell development and responsiveness to antigen stimulation [3].
• In B cells, Ship becomes associated with Fcgamma receptor IIB (FcgammaRIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)-FcgammaRIIB coligation [4].
• The function of Ship in lymphocytes was investigated in Ship-/- recombination-activating gene (Rag)-/- chimeric mice generated from gene-targeted Ship-/- embryonic stem cells [4].
• The data reveal TbetaR-mediated induction of inhibitors of antigen receptor signaling (Ship-1, CD72) as well as inhibitors of the Jak/Stat pathway and signaling by means of Toll-like receptors (SOCS1,3) [5].
• The inositol phosphatase SHIP-2 down-regulates FcgammaR-mediated phagocytosis in murine macrophages independently of SHIP-1 [6].

Biological context of Inpp5d

• In embryonic stem cells, s-SHIP partners with the adapter protein Grb2 without tyrosine phosphorylation and is present constitutively at the cell membrane [7].
• Animals lacking Src homology 2 domain-containing inositol 5-phosphatase (SHIP) display a reduction in lymphopoiesis and a corresponding enhancement of myelopoiesis [8].
• Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1 [9].
• FcgammaRIIB-mediated inhibition of Kit-dependent cell proliferation was reduced in SHIP1-deficient mast cells, whereas inhibition of IgE-induced responses was abrogated [10].
• Src homology 2 domain-containing inositol 5-phosphatase 1 mediates cell cycle arrest by FcgammaRIIB [10].

Anatomical context of Inpp5d

• Here we demonstrate that SHIP1 negatively regulates LPS-induced inflammatory response via both phosphatase activity-dependent and -independent mechanisms in macrophages [11].
• A novel SHIP isoform of approximately 104 kd expressed in primitive stem cell populations (s-SHIP) is described [7].
• Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells [12].
• In addition to T-cell and B-cell lines, spleen, thymus and lung are shown to coexpress SHIP-1 and SHIP-2 [12].
• The current study focused on the regulation of FcgammaRIIIa-induced NK cell cytokine production by SHIP1 [13].

Associations of Inpp5d with chemical compounds

• When coaggregated with ITAM-bearing receptors, FcgammaRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5'-phosphatases SHIP1 and SHIP2, which mediate inhibition [14].
• We show here that a second tyrosine-containing motif in the intracytoplasmic domain of FcgammaRIIB is required for SHIP1/2 to be coprecipitated with the receptor [14].
• Our studies on murine SHIP1 knockout platelets have defined a major role for this enzyme in regulating integrin alpha(IIb)beta(3)-dependent phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) accumulation, necessary for a cytosolic calcium response and platelet spreading [15].
• Differences in signaling pathways and expression level of the phosphoinositide phosphatase SHIP1 between two oncogenic mutants of the receptor tyrosine kinase KIT [16].
• Utilizing a glutathione S-transferase fusion protein, we found that SHIP-1 bound to Lyn via the SHIP-1 Src homology 2 domain [17].
• Imaging reactive oxygen intermediate activities in phagosomes revealed decreased early NADPH oxidase activity in SHIP-1-deficient macrophages [18].
• Overall, activation of G protein-coupled receptors that raise cyclic AMP cause SHIP1 to be phosphorylated and stimulate its inositol phosphatase activity [19].

Physical interactions of Inpp5d

• After coaggregation, FcgammaRIIB and FcepsilonRI rapidly interact with the F-actin skeleton and engage SHIP1 and filamin-1 [20].
• Dynamic interactions of Fc gamma receptor IIB with filamin-bound SHIP1 amplify filamentous actin-dependent negative regulation of Fc epsilon receptor I signaling [20].

Regulatory relationships of Inpp5d

• Interestingly, SHIP1(-/-) mice do not display endotoxin tolerance and we have found that lipopolysaccharide-induced endotoxin tolerance is contingent on up-regulating SHIP1, through the production of autocrine-acting transforming growth factor-beta, in bone-marrow-derived macrophages and mast cells [21].

Other interactions of Inpp5d

• However, the role of SHIP1 in Toll-like receptor 4 (TLR4)-mediated lipopolysaccharide (LPS) response remains unclear [11].
• The FcgammaRIIB ITIM was proposed to be necessary and sufficient for recruiting SHIP1/2 [14].
• TEL-JAK2 expression in Ba/F3 cells results in constitutive association and tyrosine phosphorylation of Shc and Ship-1 and, consequently, recruitment of Grb2 to TEL-JAK2 [22].
• We demonstrate that mice deficient in SHIP1, SHP-1, and Btk respond to the ameliorating effects of IVIg with the same kinetics as control mice [23].
• The phosphorylation of Syk, LAT, phospholipase gamma1/2, and Srchomology 2 domain-containing protein phosphatase 2 was intact, whereas the phosphorylation of SHIP-1 was significantly reduced in the YFY mutant cells [24].

Analytical, diagnostic and therapeutic context of Inpp5d

• Methanol extracts of the hepatopancreas of mussels (Mytilus edulis) harvested at two locations (Ship Harbour and Wine Harbour) in eastern Nova Scotia, Canada, were found to be toxic to mice after intraperitoneal injection [25].

References