DELETION OF SHIP OR SHP-1 REVEALS 2 DISTINCT PATHWAYS FOR INHIBITORY SIGNALING

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.