Cutting Edge: Transmembrane Phosphoprotein Csk-Binding Protein/Phosphoprotein Associated With Glycosphingolipid-Enriched Microdomains as a Negative Feedback Regulator of Mast Cell Signaling Through the Fc#epsilon#RI

摘要

Tyrosine phosphorylation in the cytoplasmic domains of Fc#epsilon#RI 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 glyco-sphingolipid-enriched microdomains (PAG), negatively regulates Fc#epsilon#RI signaling. In rat basophilic leukemia (RBL)-2H3 cells, the levels of tyrosine sphosphorylation of Cbp/PAG and its associatio with Csk, a negative regulator for Lyn, significantly elevate immediately after aggregation of Fc#epsilon#RI. An overexpression of Cbp/PAG in RBL-2H3 cells inhibits Fc#epsilon#RI-mediated cell activation. This is accompanied with decreased levels of tyrosine phosphorylation of Fc#epsilon#RI, association of Fc#epsilon#RI with Lyn, and Fc#epsilon#RI-associated tyrosine kinase activity. These findings combined with the fact that Cbp/PAG, Lyn, and aggregated Fc#epsilon#RI aggregation Cbp/PAG down-regulates the receptor-associated Lyn activity through relocating Csk to rafts, thereby efficiently mediating feedback inhibition of Fc#epsilon#RI signaling.`