The Journal of Experimental Medicine
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Published online 1 May 2000.
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© The Rockefeller University Press, 0022-1007/2000/5/1545/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 9, May 1, 2000 1545-1554

Original Article

Differential Regulation of B Cell Development, Activation, and Death by the Src Homology 2 Domain–Containing 5' Inositol Phosphatase (Ship)

Anne Brauweilera,b, Idan Tamira,b, Joseph Dal Portoa,b, Robert J. Benschopa,b, Cheryl D. Helgasonc, R. Keith Humphriesc,d, John H. Freeda,b, and John C. Cambiera,b

a Department of Immunology, National Jewish Medical and Research Center, Denver, Colorado 80206
b Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80206
c Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada
d Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206.303-398-1225303-398-1325

cambierj{at}njc.org

Although the Src homology 2 domain–containing 5' inositol phosphatase (SHIP) is a well-known mediator of inhibitory signals after B cell antigen receptor (BCR) coaggregation with the low affinity Fc receptor, it is not known whether SHIP functions to inhibit signals after stimulation through the BCR alone. Here, we show using gene-ablated mice that SHIP is a crucial regulator of BCR-mediated signaling, B cell activation, and B cell development. We demonstrate a critical role for SHIP in termination of phosphatidylinositol 3,4,5-triphosphate (PI[3,4,5]P3) signals that follow BCR aggregation. Consistent with enhanced PI(3,4,5)P3 signaling, we find that splenic B cells from SHIP-deficient mice display enhanced sensitivity to BCR-mediated induction of the activation markers CD86 and CD69. We further demonstrate that SHIP regulates the rate of B cell development in the bone marrow and spleen, as B cell precursors from SHIP-deficient mice progress more rapidly through the immature and transitional developmental stages. Finally, we observe that SHIP-deficient B cells have increased resistance to BCR-mediated cell death. These results demonstrate a central role for SHIP in regulation of BCR signaling and B cell biology, from signal driven development in the bone marrow and spleen, to activation and death in the periphery.

Key Words: signal transduction • phosphatidylinositol 3-kinase • antigen • BCR • phosphatidylinositol 3,4,5-triphosphate

Abbreviations used in this paper: 7AAD, 7-amino-actinomycin D; BCR, B cell antigen receptor; Btk, Bruton's tyrosine kinase; [Ca2+], intracellular free calcium; HSA, heat-stable antigen; IP3, inositol 1,4,5-triphosphate; MAP, mitogen-activated protein; mIg, membrane-bound Ig; NF, nuclear factor; PI3-K, phosphatidylinositol 3-kinase; PI(3,4)P2, phosphatidylinositol 3,4-biphosphate; PI(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate; PLC, phospholipase C; SHIP, Src homology 2 domain–containing 5' inositol phosphatase; sIg, surface Ig.

© 2000 The Rockefeller University Press


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