The Inositol Polyphosphate 5-Phosphatase Ship Is a Crucial Negative Regulator of B Cell Antigen Receptor Signaling

Abstract

SummaryShip is an Src homology 2 domain containing inositol polyphosphate 5-phosphatase which has been implicated as an important signaling molecule in hematopoietic cells. In B cells, Ship becomes associated with Fc ␥ receptor IIB (Fc ␥ RIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)-Fc ␥ RIIB coligation. The function of Ship in lymphocytes was investigated in Ship Ϫ / Ϫ recombination-activating gene (Rag) Ϫ / Ϫ chimeric mice generated from gene-targeted Ship Ϫ / Ϫ embryonic stem cells. Ship Ϫ / Ϫ Rag Ϫ / Ϫ chimeras showed reduced numbers of B cells and an overall increase in basal serum Ig. Ship Ϫ / Ϫ splenic B cells displayed prolonged Ca 2 ϩ influx, increased proliferation in vitro, and enhanced mitogen-activated protein kinase (MAPK) activation in response to BCR-Fc ␥ RIIB coligation. These results demonstrate that Ship plays an essential role in Fc ␥ RIIB-mediated inhibition of BCR signaling, and that Ship is a crucial negative regulator of Ca 2 ϩ flux and MAPK activation.

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

“…The inactivation of SHIP-1 in B-cells results in enhanced proliferation in response to BCR-FcγRIIB ligation, indicating that FcγRIIB-mediated inhibition of BCR signalling is dependent on SHIP-1 [18]. The inhibition of B-cell activation by SHIP-1 might involve its 5-phosphatase activity's acting on PtdIns(3,4,5)P $ , one of its substrates in itro [9] as determined in intact cells [7].…”

“…It has been observed that SHIP-1 knock-out mice present a severe phenotype characterized by a shortened lifespan, splenomegaly and massive myeloid cell accumulation in the lungs [17]. Moreover, SHIP-1k\k splenic Bcells display prolonged Ca# + influx, increased proliferation in itro, and enhanced activation of mitogen-activated protein kinase in response to BCR-FcγRIIB ligation [18]. The cDNA of a second SHIP closely related to SHIP-1 has been cloned [19] (Figure 1).…”

“…SHIP-1 has been reported to have a role in negative signalling for receptors that regulate the immune response [5][6][7]16,18]. SHIP-2 growth-factor-induced tyrosine phosphorylation [21], its association with Shc [13,21], and its ability to hydrolyse PtdIns(3,4,5)P $ [20,21] suggest that SHIP-2 could have a similar role.…”

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

“…Some SHIP-1-null mice had a spontaneous inflammatory response in the lung, indicating that SHIP-1 is an important regulator in the lung. 2,3 Recently, it was reported that macrophages isolated from SHIP-1 −/− mice display an alternatively activated (M2) phenotype, suggesting that SHIP-1 is a negative regulator of M2 generation. 22 However, the nature of the inflammation, the cell types infiltrating the lung, and the pathologic changes in the lung are not clear.…”

“…2 Heterozygous mice (SHIP-1 +/− ) were bred to generate SHIP-1 −/− and SHIP-1 +/+ (wild-type [WT]) mice, which were used as control animals. Mice were used at 9 to 11 weeks of age.…”