D'Ambrosio D, Fong D C, Cambier J C
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO, USA.
Immunol Lett. 1996 Dec;54(2-3):77-82. doi: 10.1016/s0165-2478(96)02653-3.
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.
免疫复合物介导的抗原与B细胞上Fc受体的共连接导致抗原受体（BCR）信号传导失败，并为免疫反应的反馈调节提供了一种机制。在FcγRIIB1细胞质尾巴中发现的一个含13个氨基酸的磷酸酪氨酸序列（ITIM）介导了这种抑制作用，并与磷酸酪氨酸磷酸酶SHP1特异性结合。体外结合研究表明，磷酸化的ITIM除了与SHP1结合外，还与70 kD和160 kD的未鉴定蛋白质结合。在此，我们报告p70鉴定为SHP2，p160鉴定为含SH2的磷脂酰肌醇3,4,5-三磷酸5-磷酸酶SHIP。在BCR-FcγRIIB1共连接后，SHIP可诱导酪氨酸磷酸化。此外，我们观察到在BCR-FcγRIIB1共连接后，完整细胞中SHIP与酪氨酸磷酸化的FcγRIIB1结合。在BCR连接时，SHIP的酪氨酸磷酸化程度虽小但也很显著。这些观察结果表明，SHIP可能在FcγRIIB1依赖和非依赖的BCR信号调节中起重要作用。
