The SH2 domain-containing inositol 5 '-phosphatase (SHIP) recruits the p85subunit of phosphoinositide 3-kinase during Fc gamma RIIb1-mediated inhibition of B cell receptor signaling

Coligation of Fc gamma RIIb1 with the B cell receptor (BCR) or Fc epsilon R I on mast cells inhibits B cell or mast cell activation, Activity of the in ositol phosphatase SHIP is required for this negative signal. In vitro, SHI P catalyzes the conversion of the phosphoinositide 3-kinase (PI3K) product phosphatidylinositol 3,4,5-trisphosphate (PIP3) into phosphatidylinositol 3 ,4-bisphosphate. Recent data demonstrate that coligation of Fc gamma RIIb1 with BCR inhibits PIP3-dependent Btk (Bruton's tyrosine kinase) activation and the Btk-dependent generation of inositol trisphosphate that regulates s ustained calcium influx, In this study, we provide evidence that coligation of Fc gamma RIIb1 with BCR induces binding of PI3K to SHIP, This interacti on is mediated by the binding of the SH2 domains of the p85 subunit of PI3K to a tyrosine-based motif in the C-terminal region of SHIP. Furthermore, t he generation of phosphatidylinositol 3,4-bisphosphate was only partially r educed during coligation of BCR with Fc gamma RIIb1 despite a drastic reduc tion in PIP3. In contrast to the complete inhibition of Tec kinase-dependen t calcium signaling, activation of the serine/threonine kinase Akt was part ially preserved during BCR and Fc gamma RIIb1 coligation, The association o f PI3K with SHIP may serve to activate PI3K and to regulate downstream even ts such as B cell activation-induced apoptosis.