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The Journal of Immunology, 2002, 168: 2087-2090.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

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

Hidenori Ohtake*, Naoki Ichikawa*, Masato Okada{dagger} and Toshiyuki Yamashita1,*

* Division of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; and {dagger} Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

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 glycosphingolipid-enriched microdomains (PAG), negatively regulates Fc{epsilon}RI 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 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 are localized to lipid rafts, suggest that upon 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.




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