Cutting edge:: Transmembrane phosphoprotein Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains as a negative feedback regulator of mast cell signaling through the FcεRI

Tyrosine phosphorylation in the cytoplasmic domains of Fcis an element ofRI by the Src family kinase Lyn initiates a signaling cascade leading to mast cell activation. In this study, we show that a recently identified transmembrane protein, Csk-binding protein (Cbp), also known as phospoprotein associated with glycosphingolipid-enriched microdomains (PAG), negatively regulates Fcis an element ofRI signaling. In rat basophilic leukemia (RBL)-2H3 cells, the levels of tyrosine phosphorylation of Cbp/PAG and its association with Csk, a negative regulator for Lyn, significantly elevate immediately after aggregation of Fcis an element ofRI. An overexpression of Cbp/PAG in RBL-2H3 cells inhibits Fcis an element ofRI-mediated cell activation. This is accompanied with decreased levels of tyrosine phosphorylation of Fcis an element ofRI, association of Fcis an element ofRI with Lyn, and Fcis an element ofRI-associated tyrosine kinase activity. These findings combined with the fact that Cbp/PAG, Lyn, and aggregated Fcis an element ofRI are localized to lipid rafts, suggest that upon Fcis an element ofRI aggregation Cbp/PAG down-regulates the receptor-associated Lyn activity through relocating Csk to rafts, thereby efficiently mediating feedback inhibition of Fcis an element ofRI signaling.