title: An extracatalytic function of CD45 in B cells is mediated by CD22.
abstract: The receptor-like tyrosine phosphatase CD45 regulates antigen receptor signaling by dephosphorylating the C-terminal inhibitory tyrosine of the src family kinases. However, despite its abundance, the function of the large, alternatively spliced extracellular domain of CD45 has remained elusive. We used normally spliced CD45 transgenes either incorporating a phosphatase-inactivating point mutation or lacking the cytoplasmic domain to uncouple the enzymatic and noncatalytic functions of CD45 in lymphocytes. Although these transgenes did not alter T-cell signaling or development irrespective of endogenous CD45 expression, both partially rescued the phenotype of CD45-deficient B cells. We identify a noncatalytic role for CD45 in regulating tonic, but not antigen-mediated, B-cell antigen receptor (BCR) signaling through modulation of the function of the inhibitory coreceptor CD22. This finding has important implications for understanding how naïve B cells maintain tonic BCR signaling while restraining inappropriate antigen-dependent activation to preserve clonal "ignorance."
authors.affiliation: Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, CA 94143; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143;
authors.forename: Sarah
authors.initials: S
authors.lastname: Coughlin
authors.affiliation: Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, CA 94143;
authors.forename: Mark
authors.initials: M
authors.lastname: Noviski
authors.affiliation: Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, CA 94143;
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.affiliation: Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, CA 94143;
authors.forename: Ammarina
authors.initials: A
authors.lastname: Chuwonpad
authors.affiliation: Virogenics Inc., San Diego, CA 92121.
authors.forename: William C
authors.initials: WC
authors.lastname: Raschke
authors.affiliation: Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, CA 94143; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143; julie.zikherman@ucsf.edu art.weiss@ucsf.edu.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, CA 94143; julie.zikherman@ucsf.edu art.weiss@ucsf.edu.
authors.forename: Julie
authors.initials: J
authors.lastname: Zikherman
mesh_terms: D000483:Alleles; D000818:Animals; D000941:Antigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D055162:Biocatalysis; D000081247:CSK Tyrosine-Protein Kinase; D002118:Calcium / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D060168:Thymocytes / Q000378:metabolism; D019076:Transgenes; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000941:Antigens; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens; D002118:Calcium
keywords: B-cell development; BCR signaling; CD22; CD45; TCR signaling