title: Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy.
abstract: Anergic B cells are characterized by impaired signaling and activation after aggregation of their antigen receptors (BCR). The molecular basis of this impairment is not understood. In studies reported here, Src homology-2 (SH2)-containing inositol 5-phosphatase SHIP-1 and its adaptor Dok-1 were found to be constitutively phosphorylated in anergic B cells, and activation of this inhibitory circuit was dependent on Src-family kinase activity and consequent to biased BCR immunoreceptor tyrosine-based activation motif (ITAM) monophosphorylation. B cell-targeted deletion of SHIP-1 caused severe lupus-like disease. Moreover, absence of SHIP-1 in B cells led to loss of anergy as indicated by restoration of BCR signaling, loss of anergic surface phenotype, and production of autoantibodies. Thus, chronic BCR signals maintain anergy in part via ITAM monophosphorylation-directed activation of an inhibitory signaling circuit involving SHIP-1 and Dok-1.
authors.affiliation: Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, CO 80206, USA.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: O'Neill
authors.forename: Andrew
authors.initials: A
authors.lastname: Getahun
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gauld
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Merrell
authors.forename: Idan
authors.initials: I
authors.lastname: Tamir
authors.forename: Mia J
authors.initials: MJ
authors.lastname: Smith
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Dal Porto
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051925:CD79 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018390:Gene Targeting; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D008822:Mice, Transgenic; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051925:CD79 Antigens; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D014443:Tyrosine; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
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