Membrane-targeted peptides derived from Igalpha attenuate B-cell antigen receptor function.
Within the B-cell antigen receptor (BCR), heterodimers of Igalpha/Igbeta couple the receptor to intracellular signaling pathways. In the resting state, Igalpha associates with Src-family tyrosine kinases (SFTKs) which contain some basal activity. Upon engagement of the receptor, the SFTKs phosphorylate tyrosine residues in the BCR that recruit and activate the tyrosine kinase Syk, initiating signaling pathways. To test the hypothesis that disrupting the association between the resting receptor and the SFTKs would attenuate both basal and induced receptor activities, we expressed non-phosphorylatable membrane-targeted analogs of Igalpha (Igalpha/M) or Igbeta (Igbeta/M) in B lymphocytes. Both Igalpha/M and Igbeta/M inhibited BCR-induced calcium mobilization, but only Igalpha/M was able to diminish tyrosine phosphorylation. In an immature B-cell line, Igalpha/M attenuated both receptor-induced and basal apoptosis. Taken together, these data demonstrate the importance of the resting receptor complex and suggest therapeutic strategies for regulating receptor-mediated functions.
Kabak
Shara
S
Departments of Medicine and Pathology, Section of Rheumatology, Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
Clark
Marcus R
MR
D015703:Antigens, CD / Q000737:chemistry*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051925:CD79 Antigens; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D015703:Antigens, CD; D051925:CD79 Antigens; D010455:Peptides; D011947:Receptors, Antigen, B-Cell; D002118:Calcium