THE SHIP PHOSPHATASE BECOMES ASSOCIATED WITH FC-GAMMA-RIIB1 AND IS TYROSINE-PHOSPHORYLATED DURING NEGATIVE SIGNALING

Immune-complex mediated co-ligation of antigen and Fe receptors on B-c ells leads to abortive antigen receptor (BCR) signaling and provides a mechanism for feedback regulation of the immune response. A phosphoty rosine-containing 13 amino acid sequence (ITIM) found in the Fc gamma RIIB1 cytoplasmic tail mediates this inhibition and specifically assoc iates with the phosphotyrosine phosphatase SHP1. In vitro binding stud ies demonstrate that the phosphorylated ITIM binds unidentified protei ns of 70 and 160 kD in addition to SHP1. Here we report the identifica tion of p70 as SHP2 and p160 as the SH2 containing phosphatidylinosito l 3,4,5-trisphosphate 5-phosphatase SHIP. SHIP is inducibly tyrosine p hosphorylated following BCR-Fc gamma RIIB1 co-ligation. Further, we ob serve SHIP association with tyrosine phosphorylated Fc gamma RIIB1 in intact cells following BCR-Fc gamma RIIB1 co-ligation. To a much lesse r but significant degree, tyrosine phosphorylation of SHIP is also obs erved upon BCR ligation. These observations suggest that SHIP may play an important role in Fc gamma RIIB1 dependent and independent regulat ion of BCR signaling. (C) 1996 Elsevier Science B.V.