The Journal of Experimental Medicine
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Published online 10 November 2003 doi:10.1084/jem.20011866
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© Rockefeller University Press, 0022-1007/2003/11/1539 $5.00
The Journal of Experimental Medicine, Volume 198, Number 10, 1539-1550

The B Cell Antigen Receptor Controls Integrin Activity through Btk and PLC{gamma}2

Marcel Spaargaren1, Esther A. Beuling1, Mette L. Rurup1, Helen P. Meijer1, Melanie D. Klok1, Sabine Middendorp2, Rudolf W. Hendriks2 and Steven T. Pals1

1 Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, Netherlands
2 Department of Immunology, Erasmus MC, 3000 DR Rotterdam, Netherlands

Address correspondence to: Marcel Spaargaren, Dept. of Pathology, Academic Medical Center, Meibergdreef 9 1105 AZ Amsterdam, Netherlands. Phone: 31-20-5665635; Fax: 31-20-6960389. email: marcel.spaargaren{at}amc.uva.nl

Integrin-mediated adhesion and B cell antigen receptor (BCR) signaling play a critical role in B cell development and function, including antigen-specific B cell differentiation. Here we show that the BCR controls integrin {alpha}4ß1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 and fibronectin. Molecular dissection of the underlying signaling mechanism by a combined biochemical, pharmacological, and genetic approach demonstrates that this BCR-controlled integrin-mediated adhesion requires the (consecutive) activation of Lyn, Syk, phosphatidylinositol 3-kinase, Bruton's tyrosine kinase (Btk), phospholipase C (PLC){gamma}2, IP3R-mediated Ca2+ release, and PKC. In contrast, activation of mitogen-activated protein kinase kinase (MEK) or extracellular signal–regulated kinase (ERK) is not required, and simultaneous activation of MEK, ERK, and PKB is not sufficient either. Furthermore, Btk is also involved in the control of integrin-mediated adhesion of preB cells. The control of integrin {alpha}4ß1-mediated B cell adhesion by the BCR involves cytoskeletal reorganization and integrin clustering. These results reveal a novel function for the BCR and Btk, i.e., regulation of integrin {alpha}4ß1 activity, thereby providing new insights into the control of B cell development and differentiation, as well as into the pathogenesis of the immunodeficiency disease X-linked agammaglobulineamia (XLA).

Key Words: lymphocyte adhesion • B-cell development • X-linked agammaglobulinaemia • germinal center • VCAM-1


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