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

doi:10.1084/jem.188.7.1333

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J. Exp. Med., Volume 188, Number 7, October 5, 1998 1333-1342

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

By 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 importantsignaling molecule in hematopoietic cells. In B cells, Ship becomesassociated with Fc $gamma$ receptor IIB (Fc $gamma$ RIIB), a low affinity receptorfor the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosinephosphorylated upon B cell antigen receptor (BCR)-Fc $gamma$ RIIB 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 increasein basal serum Ig. Ship^/ splenic B cells displayed prolonged Ca²⁺ influx, increased proliferation in vitro, and enhanced mitogen-activatedprotein kinase (MAPK) activation in response to BCR-Fc $gamma$ RIIB coligation.These results demonstrate that Ship plays an essential role inFc $gamma$ RIIB-mediated inhibition of BCR signaling, and that Ship isa crucial negative regulator of Ca²⁺ flux and MAPK activation.

Key words: inositol phosphatase; Fc $gamma$ receptor IIB inhibitory signal; signal transduction; B cell antigen receptor signaling; gene targeting

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