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J Biol Chem, Vol. 274, Issue 11, 7489-7494, March 12, 1999

The SH2 Domain-containing Inositol 5'-Phosphatase (SHIP) Recruits the p85 Subunit of Phosphoinositide 3-Kinase during FcRIIb1-mediated Inhibition of B Cell Receptor Signaling

Neetu Gupta, Andrew M. Scharenberg^§, David A. Fruman^¶, Lewis C. Cantley^¶, Jean-Pierre Kinet^§, and Eric O. Long

From the  Laboratory of Immunogenetics, NIAID, National Institutes of Health, Rockville, Maryland 20852-1727 and the Laboratories of ^§ Allergy and Immunology and ^¶ Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Coligation of FcRIIb1 with the B cell receptor (BCR) or FcRI on mast cells inhibits B cell or mast cell activation. Activity of the inositol phosphatase SHIP is required for this negative signal. In vitro, SHIP 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 FcRIIb1 with BCR inhibits PIP₃-dependent Btk (Bruton's tyrosine kinase) activation and the Btk-dependent generation of inositol trisphosphate that regulates sustained calcium influx. In this study, we provide evidence that coligation of FcRIIb1 with BCR induces binding of PI3K to SHIP. This interaction 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, the generation of phosphatidylinositol 3,4-bisphosphate was only partially reduced during coligation of BCR with FcRIIb1 despite a drastic reduction in PIP₃. In contrast to the complete inhibition of Tec kinase-dependent calcium signaling, activation of the serine/threonine kinase Akt was partially preserved during BCR and FcRIIb1 coligation. The association of PI3K with SHIP may serve to activate PI3K and to regulate downstream events such as B cell activation-induced apoptosis.

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