THE INOSITOL POLYPHOSPHATE 5-PHOSPHATASE SHIP IS A CRUCIAL NEGATIVE REGULATOR OF B-CELL ANTIGEN RECEPTOR SIGNALING

Ship is an Src homology 2 domain containing inositol polyphosphate 5-p hosphatase which has been implicated as an important signaling molecul e in hematopoietic cells. In B cells, Ship becomes associated with Fc gamma receptor IIB (Fc gamma RIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylat ed upon B cell antigen receptor (BCR)-Fc gamma RIIB coligation. The fu nction of Ship in lymphocytes was investigated in Ship(-/-) recombinat ion-activating gene (Rag)(-/-) chimeric mice generated from gene-targe ted Ship(-/-) embryonic stem cells. Ship(-/-)Rag(-/-) chimeras showed reduced numbers of B cells and an overall increase in basal serum Ig. Ship(-/-) splenic B cells displayed prolonged Ca2+ influx, increased p roliferation in vitro, and enhanced mitogen-activated protein kinase ( MAPK) activation in response to BCR-Fc gamma RIIB coligation. These re sults demonstrate that Ship plays an essential role in Fc gamma RIIB-m ediated inhibition of BCR signaling, and that Ship is a crucial negati ve regulator of Ca2+ flux and MAPK activation.