The SHIP phosphatase becomes associated with Fc gammaRIIB1 and is tyrosine phosphorylated during 'negative' signaling.
Immune-complex mediated co-ligation of antigen and Fc receptors on B-cells leads to abortive antigen receptor (BCR) signaling and provides a mechanism for feedback regulation of the immune response. A phosphotyrosine-containing 13 amino acid sequence (ITIM) found in the FcgammaRIIB1 cytoplasmic tail mediates this inhibition and specifically associates with the phosphotyrosine phosphatase SHP1. In vitro binding studies demonstrate that the phosphorylated ITIM binds unidentified proteins of 70 and 160 kD in addition to SHP1. Here we report the identification of p70 as SHP2 and p160 as the SH2 containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase SHIP. SHIP is inducibly tyrosine phosphorylated following BCR-FcgammaRIIB1 co-ligation. Further, we observe SHIP association with tyrosine phosphorylated FcgammaRIIB1 in intact cells following BCR-FcgammaRIIB1 co-ligation. To a much lesser but significant degree, tyrosine phosphorylation of SHIP is also observed upon BCR ligation. These observations suggest that SHIP may play an important role in FcgammaRIIB1 dependent and independent regulation of BCR signaling.
D'Ambrosio
D
D
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO, USA.
Fong
D C
DC
Cambier
J C
JC
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000276:immunology*; D010766:Phosphorylation; D011485:Protein Binding; D017452:Receptors, IgG / Q000276:immunology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000276:immunology*; D018909:src Homology Domains / Q000276:immunology*
D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D014443:Tyrosine; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases