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Anne Mette Buhl^*, Christopher M. Pleiman, Robert C. Rickert^||, and John C. Cambier^*,

From the ^* Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206; Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80206; Cadus Pharmaceuticals, 1601 Pierce St., Suite 110, Lakewood, Colorado 80214; and ^|| Department of Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0322

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.

¹ Abbreviations used in this paper: BCR, B cell antigen receptor; IP₃, inositol-1,4,5-trisphosphate; ITAM, immunoreceptor tyrosine based activation motif; NP, nitrophenol; PH, pleckstrin homology; PI, phosphatidylinositol; PI3-kinase, phosphatidylinositol 3-kinase.

A.M. Buhl is a Leukemia Society Research Fellow. J.C. Cambier is an Ida and Cecil Green Professor of Cell Biology. These studies were supported by the US Public Health Service.

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• Craxton, A., Jiang, A., Kurosaki, T., Clark, E. A. (1999). Syk and Bruton's Tyrosine Kinase Are Required for B Cell Antigen Receptor-mediated Activation of the Kinase Akt. J. Biol. Chem. 274: 30644-30650 [Abstract] [Full Text]  
• Benschop, R. J., Melamed, D., Nemazee, D., Cambier, J. C. (1999). Distinct Signal Thresholds for the Unique Antigen Receptor-Linked Gene Expression Programs in Mature and Immature B Cells. JEM 190: 749-756 [Abstract] [Full Text]  
• Gold, M. R., Scheid, M. P., Santos, L., Dang-Lawson, M., Roth, R. A., Matsuuchi, L., Duronio, V., Krebs, D. L. (1999). The B Cell Antigen Receptor Activates the Akt (Protein Kinase B)/Glycogen Synthase Kinase-3 Signaling Pathway Via Phosphatidylinositol 3-Kinase. J. Immunol. 163: 1894-1905 [Abstract] [Full Text]  
• Buhl, A. M., Cambier, J. C. (1999). Phosphorylation of CD19 Y484 and Y515, and Linked Activation of Phosphatidylinositol 3-Kinase, Are Required for B Cell Antigen Receptor-Mediated Activation of Bruton's Tyrosine Kinase. J. Immunol. 162: 4438-4446 [Abstract] [Full Text]  
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• Gratacap, M.-P., Payrastre, B., Viala, C., Mauco, G., Plantavid, M., Chap, H. (1998). Phosphatidylinositol 3,4,5-Trisphosphate-dependent Stimulation of Phospholipase C-gamma 2 Is an Early Key Event in Fcgamma RIIA-mediated Activation of Human Platelets. J. Biol. Chem. 273: 24314-24321 [Abstract] [Full Text]  
• Otero, D. C., Omori, S. A., Rickert, R. C. (2001). CD19-dependent Activation of Akt Kinase in B-lymphocytes. J. Biol. Chem. 276: 1474-1478 [Abstract] [Full Text]  
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