Differential regulation of B cell development, activation, and death by the Src homology 2 domain-containing 5 ' inositol phosphatase (SHIP)

Although the Src homology 2 domain-containing 5' inositol phosphatase (SHIP ) is a well-known mediator of inhibitory signals after B cell antigen recep tor (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 regula tor of BCR-mediated signaling, B cell activation, and B cell development. W e demonstrate a critical role for SHIP in termination of phosphatidylinosit ol 3,4,5-triphosphate (PI[3,4,5]P-3) signals that follow BCR aggregation. C onsistent with enhanced PI(3,4,5)P-3 signaling, we find that splenic B cell s from SHIP-deficient mice display enhanced sensitivity to BCR-mediated ind uction of the activation markers CD86 and CD69. We further demonstrate that SHIP regulates the rate of B cell development in the bone marrow and splee n, as B cell precursors from SHIP-deficient mice progress more rapidly thro ugh 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 bon e marrow and spleen, to activation and death in the periphery.