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© The Rockefeller University Press, 0022-1007/1998/10/1333/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 7, October 5, 1998 1333-1342

Articles

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

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

From the * Amgen Institute, Toronto, Ontario, Canada M5G 2C1; the {ddagger} 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{gamma} receptor IIB (Fc{gamma}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{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 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–Fc{gamma}RIIB coligation. These results demonstrate that Ship plays an essential role in Fc{gamma}RIIB-mediated inhibition of BCR signaling, and that Ship is a 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

Address correspondence to Qiurong Liu, Amgen Institute, 620 University Avenue, Suite 706, Toronto, Canada, M5G 2C1. Phone: 416-204-2264; Fax: 416-204-2277; E-mail: qliu{at}amgen.com

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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