Qualitative regulation of B cell antigen receptor signaling by CD19: selective requirement for PI3-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization.
Genetic ablation of the B cell surface glycoprotein CD19 severely impairs the humoral immune response. This requirement is thought to reflect a critical role of CD19 in signal transduction that occurs upon antigen C3dg coligation of antigen receptors with CD19 containing type 2 complement receptors (CR2). Here we show that CD19 plays a key accessory role in B cell antigen receptor signaling independent of CR2 coligation and define molecular circuitry by which this function is mediated. While CD19 is not required for antigen-mediated activation of receptor proximal tyrosines kinases, it is critical for activation of phosphatidylinositol 3-kinase (PI3-kinase). PI3-Kinase activation is dependent on phosphorylation of CD19 Y484 and Y515. Antigen-induced CD19-dependent PI3-kinase activation is required for normal phosphoinositide hydrolysis and Ca2+ mobilization responses. Thus, CD19 functions as a B cell antigen receptor accessory molecule that modifies antigen receptor signaling in a qualitative manner.
Buhl
A M
AM
Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206, USA.
Pleiman
C M
CM
Rickert
R C
RC
Cambier
J C
JC
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D018941:Antigens, CD19 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D002118:Calcium / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis / Q000502:physiology*; D007424:Intracellular Fluid / Q000378:metabolism; D012515:Mast-Cell Sarcoma / Q000473:pathology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D018941:Antigens, CD19; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins; D015544:Inositol 1,4,5-Trisphosphate; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D002118:Calcium; D000077191:Wortmannin