Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1

Coligation of paired immunoglobulin-like receptor B (PIR-B) with B cell antigen receptor (BCR) blocks antigen-induced B cell activation. This inhibition is mediated in part by recruitment of SHP-1 and SHP-2 to the phosphorylated ITIMs in the cytoplasmic domain of PIR-B; however the molecular target(s) of these phosphatases remain elusive. Here,ve show that PIR-B ligation inhibits the BCR-induced tyrosine phosphorylation of Ig alpha/Ig beta, Syk, Btk and phospholipase C (PLC)-gamma 2 Overexpression of a catalgtically inactive form of SHP-1 prevents the PIR-B-mediated inhibition: of tyrosine phosphorylation of Syk, Btk, and PLC-gamma 2. Dephosphorylation of Syk and Btk mediated by SHP-1 leads to a decrease of their kinase activity, which in turn inhibits tyrosine phosphorylation of PLC-gamma 2. Furthermore, we define a requirement for Lan in mediating tyrosine phosphorylation of PIR-B, Based on these results, we propose a model of PIR-B-mediated inhibitory signaling in which coligation of PIR-B and BCR results in phosphorylation of ITIMs by Lyn, subsequent recruitment of SHP-1, and a resulting inhibition of the BCR-induced inositol 1,4,5-trisphosphate generation by dephosphorylation of Syk and Btk.