Grb2 and the non-T cell activation linker NTAL constitute a Ca(2+)-regulating signal circuit in B lymphocytes

Immunity. 2004 Nov;21(5):681-91. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • B-Lymphocytes / metabolism*
  • Base Sequence
  • Calcium / metabolism*
  • Carrier Proteins / physiology
  • Cells, Cultured
  • Chickens
  • GRB2 Adaptor Protein
  • Membrane Microdomains / metabolism
  • Molecular Sequence Data
  • Phospholipase C gamma
  • Phosphoproteins / physiology
  • Signal Transduction
  • Type C Phospholipases / physiology


  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • Carrier Proteins
  • GRB2 Adaptor Protein
  • Phosphoproteins
  • Type C Phospholipases
  • Phospholipase C gamma
  • Calcium

Associated data

  • GENBANK/AY743659