The B cell antigen receptor controls integrin activity through Btk and PLCgamma2.
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 alpha4beta1 (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)gamma2, 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 alpha4beta1-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 alpha4beta1 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).
Spaargaren
Marcel
M
Dept. of Pathology, Academic Medical Center, Meibergdreef 9 1105 AZ Amsterdam, Netherlands. marcel.spaargaren@amc.uva.nl
Beuling
Esther A
EA
Rurup
Mette L
ML
Meijer
Helen P
HP
Klok
Melanie D
MD
Middendorp
Sabine
S
Hendriks
Rudolf W
RW
Pals
Steven T
ST
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002118:Calcium; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000077329:Agammaglobulinaemia Tyrosine Kinase; D002118:Calcium; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D016023:Integrins; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D011947:Receptors, Antigen, B-Cell; D010738:Type C Phospholipases; D019010:Vascular Cell Adhesion Molecule-1; C112986:AIF1 protein, human; C000625949:BTK protein, human; C000625951:Btk protein, mouse