The effect of phosphatases SHP-1 and SHIP-1 on signaling by the ITIM- and ITAM-containing Fc receptors Fc RIIB and Fc RIIA

Inositol and tyrosine phosphatases have been implicated in inhibitory signaling by an Fc receptor for immunoglobulin G, Fc RIIB, in B cells, mast cells, and monocytes. Here, we propose a role for the Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1) in Fc RIIB-mediated inhibition of Fc R signaling. Coexpression of SHP-1 enhances Fc RIIB-mediated inhibition of Fc RIIA phagocytosis in COS-1 cells. SHP-1 also enhances the reduction in Fc RIIA tyrosine phosphorylation that accompanies this inhibition. Significantly, tyrosine phosphorylation of Syk kinase is substantially inhibited by SHP-1. Furthermore, the activation of SHP-1 tyrosine phosphorylation is observed following stimulation of Fc RII in COS-1 cells and in human monocytes. The SH2 domain containing inositol phosphatase (SHIP), SHIP-1 also enhances Fc RIIB-mediated inhibition of Fc RIIA, indicating that Fc RIIB can use more than one pathway for its inhibitory action. In addition, SHP-1 and SHIP-1 can inhibit Fc RIIA phagocytosis and signal transduction in the absence of Fc RIIB. The data support emerging evidence that SH2-containing phosphatases, such as SHP-1 and SHIP-1, can modulate signaling by “activating” receptors. J. Leukoc. Biol. 73: 823–829; 2003.