Grb2 and the Non-T Cell Activation Linker NTAL Constitute a Ca2+-Regulating Signal Circuit in B Lymphocytes

• Published in: Immunity (Cambridge, Mass.) Mass.), 2004-11, Vol.21 (5), p.681-691
• Main Authors: Stork, Björn, Engelke, Michael, Frey, Jürgen, Horejsı́, Václav, Hamm-Baarke, Andrea, Schraven, Burkhart, Kurosaki, Tomohiro, Wienands, Jürgen
• Format: Article
• Language: English
• Subjects: Binding sites; Cloning; Enzymes; Immune system; Kinases; Lipids; Lymphocytes; Phosphorylation; Plasma; Proteins; Rodents
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2004.09.007

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 Ca2+-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 Ca2+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 Ca2+and is mandatory for subsequent entry of Ca2+from extracellular sources. Thus, elevation of Ca2+is regulated by at least two signaling modules, the B cell-specific Ca2+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.