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Qiurong Liu^*, Antonio J. Oliveira-Dos-Santos^*, Sanjeev Mariathasan, Denis Bouchard^*, Jamie Jones^*, Renu Sarao^*, Ivona Kozieradzki^*, Pamela S. Ohashi^,,||, Josef M. Penninger^*,,, and Daniel J. Dumont^*,

From the ^* Amgen Institute, Toronto, Ontario, Canada M5G 2C1; the Department of Medical Biophysics and the Department of Immunology, University of Toronto, Ontario, Canada M5G 2M9; and the ^|| Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2M9

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 Fc receptor IIB (FcRIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)–FcRIIB 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 of B 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–FcRIIB coligation. These results demonstrate that Ship plays an essential role in FcRIIB-mediated inhibition of BCR signaling, and that Ship is a crucial negative regulator of Ca²⁺ flux and MAPK activation.

Key Words: inositol phosphatase • Fc receptor IIB inhibitory signal • signal transduction • B cell antigen receptor signaling • gene targeting

Abbreviations used: BCR, B cell antigen receptor; ERK, extracellular signal–regulated protein kinase; ES, embryonic stem; FBS, fetal bovine serum; Grb, growth factor receptor–bound protein; HSA, heat stable antigen; ICAM, intracellular adhesion molecule; IP4, inositol-1,3,4,5-polyphosphate; ITIM, immunoreceptor tyrosine–based inhibitory motif; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; PIP3, phosphatidylinositol-3,4,5-polyphosphate; Rag, recombination-activating gene; SAPK, stress-activated protein kinase; SH, Src homology domain; Ship, SH2-containing inositol polyphosphate 5-phosphatase; SHP, SH2-containing protein tyrosine phosphatase; VSV, vesicular stomatitis virus.

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