Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms.
The regulation of receptor-like protein tyrosine phosphatases (RPTPs) is not well understood. Although CD45 can be negatively regulated by dimerization, how dimerization is modulated is unclear. Here we show that various isoforms of CD45 differentially homodimerize in T cells. The dimerization is modulated by the sialylation and O-glycosylation of alternatively spliced CD45 exons in the extracellular domain. Thus, the smallest isoform, CD45RO--which undergoes the least extracellular sialylation and O-glycosylation--homodimerizes with the highest efficiency, resulting in decreased signaling via the T cell receptor. Because CD45 is required for T cell activation, our findings may reveal a mechanism that contributes to the termination of the primary T cell response. Our results not only demonstrate the biological significance of alternative splicing in the immune system, but also suggest a model for regulating RPTP dimerization and function.
Department of Medicine and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94143-0795, USA.
Zheng
Z
Xu
Arthur
A
Weiss
D017398:Alternative Splicing / Q000235:genetics / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015080:Mesna / Q000737:chemistry; D051379:Mice; D016296:Mutagenesis; D009439:Neuraminidase / Q000737:chemistry; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D020033:Protein Isoforms; D017493:Leukocyte Common Antigens; D017027:Protein Tyrosine Phosphatases; D009439:Neuraminidase; D015080:Mesna