Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes

Stork B, Engelke M, Frey J, Horejsi V, Hamm-Baarke A, Schraven B, Kurosaki T, Wienands J (2004)
IMMUNITY 21(5): 681-691.

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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-gamma2. 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-gamma2 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-gamma2 and the more ubiquitously expressed NTAL/Grb2 complex, which acts as an amplifier by switching off inhibitory elements.
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Stork B, Engelke M, Frey J, et al. Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes. IMMUNITY. 2004;21(5):681-691.
Stork, B., Engelke, M., Frey, J., Horejsi, V., Hamm-Baarke, A., Schraven, B., Kurosaki, T., et al. (2004). Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes. IMMUNITY, 21(5), 681-691. doi:10.1016/j.immuni.2004.09.007
Stork, B., Engelke, M., Frey, J., Horejsi, V., Hamm-Baarke, A., Schraven, B., Kurosaki, T., and Wienands, J. (2004). Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes. IMMUNITY 21, 681-691.
Stork, B., et al., 2004. Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes. IMMUNITY, 21(5), p 681-691.
B. Stork, et al., “Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes”, IMMUNITY, vol. 21, 2004, pp. 681-691.
Stork, B., Engelke, M., Frey, J., Horejsi, V., Hamm-Baarke, A., Schraven, B., Kurosaki, T., Wienands, J.: Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes. IMMUNITY. 21, 681-691 (2004).
Stork, B, Engelke, M, Frey, Jürgen, Horejsi, V, Hamm-Baarke, A, Schraven, B, Kurosaki, T, and Wienands, J. “Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes”. IMMUNITY 21.5 (2004): 681-691.
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