The inositol polyphosphate 5-phosphatase ship is a crucial negative regulator of B cell antigen receptor signaling

Abstract

Ship 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 Fcγ receptor IIB (FcγRIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)-FcγRIIB coligation. The function of Ship in lymphocytes was investigated in Ship(-/-) recombination-activating gene (Rag)(-/-) chimeric mice generated from gene-targeted Ship(-/-) embryonic stem cells. Ship(-/- )Rag(-/-) chimeras showed reduced numbers orb cells and an overall increase in basal serum Ig. Ship(-/-) splenic B cells displayed prolonged Ca2+ influx, increased proliferation in vitro, and enhanced mitogen-activated protein kinase (MAPK) activation in response to BCR-FcγRIIB coligation. These results demonstrate that Ship plays an essential role in FcγRIIB- mediated inhibition of BCR signaling, and that Ship is a crucial negative regulator of Ca2+ flux and MAPK activation.