Grb2 and the non-T cell activation linker NTAL constitute a Ca(2+)-regulating signal circuit in B lymphocytes.
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-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 Ca(2+) 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 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-gamma2 and the more ubiquitously expressed NTAL/Grb2 complex, which acts as an amplifier by switching off inhibitory elements.
Stork
Björn
B
Department of Biochemistry and Molecular Immunology, University of Bielefeld, 33615 Bielefeld, Germany.
Engelke
Michael
M
Frey
Jürgen
J
Horejsí
Václav
V
Hamm-Baarke
Andrea
A
Schraven
Burkhart
B
Kurosaki
Tomohiro
T
Wienands
Jürgen
J
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D002645:Chickens; D051380:GRB2 Adaptor Protein; D021962:Membrane Microdomains / Q000378:metabolism; D008969:Molecular Sequence Data; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000502:physiology; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D051380:GRB2 Adaptor Protein; D010750:Phosphoproteins; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium