Two signaling molecules have been implicated in the modulation of immu
ne receptor activation by inhibitory coreceptors: an inositol polyphos
phate 5'-phosphatase, SHIP, and a tyrosine phosphatase, SHP-1. To addr
ess the necessity, interaction, or redundancy of these signaling molec
ules, we have generated SHP-1-or SHIP-deficient B cell lines and deter
mined their ability to mediate inhibitory signaling. Two distinct clas
ses of inhibitory responses are defined, mediated by the selective rec
ruitment of SHP-1 or SHIP. The Fc gamma RIIB class of inhibitory signa
ling is dependent on SHIP and not SHP-1; conversely, the KIR class req
uires SHP-1 and not SHIP. The consequence of this selective recruitmen
t by inhibitory receptor engagement is seen in BCR-triggered apoptosis
. SHP-1-mediated inhibitory signaling blocks apoptosis, while SHIP rec
ruitment attenuates a proapoptotic signal initiated by Fc gamma RIIB.