Abstract
Activation of the B cell antigen receptor triggers phosphorylation of cytoplasmic and transmembrane adaptor proteins such as SLP-65 and NTAL, respectively. Specific phosphoacceptor sites in SLP-65 serve as docking sites for Ca 2+-mobilizing enzymes Btk and PLC-γ2. Phosphorylated NTAL recruits the Grb2 linker, but downstream signaling cascades are unclear. We now show that receptor-induced tyrosine phosphorylation of NTAL and concomitant Grb2 complex formation critically modulate the Ca 2+ response without affecting SLP-65 and PLC-γ2 phosphorylation. Grb2 turned out to play a negative regulatory role, which appears to be eliminated upon binding to NTAL. This allows for a sustained release of intracellular Ca 2+ and is mandatory for subsequent entry of Ca 2+ from extracellular sources. Thus, elevation of Ca 2+ is regulated by at least two signaling modules, the B cell-specific Ca 2+ initiation complex comprising SLP-65, Btk, and PLC-γ2 and the more ubiquitously expressed NTAL/Grb2 complex, which acts as an amplifier by switching off inhibitory elements.
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