The cytoplasmic tail of Fcγ/RIIIAα is involved in signaling by the low affinity receptor for immunoglobulin G

Abstract

The low affinity receptor for IgG, FcγRIIIA, is a multimeric receptor composed of the ligand binding subunit FcγRIIIAα (CD16) in association with the signal-transducing subunits ζ or γ. Previous studies suggested that the cytoplasmic tail of FcγRIIIAα was not required for FcγRIIIAα-ζ association or signaling by FcγRIIIA. However, in these studies, the truncated FcγRIIIAα chains still expressed the four most membrane-proximal amino acids of the cytoplasmic tail (amino acids 230-233). By successive truncations from the C terminus of FcγRIIIAα, we have studied the role played by the membrane-proximal amino acids of the cytoplasmic tail of FcγRIIIAα in (i) FcγRIIIA expression, (ii) FcγRIIIAα-ζ association, and (iii) signal transduction. We provide evidence that this region is not required for FcγRIIIA expression or FcγRIIIAα-ζ association. However, signaling by FcγRIIIA is strictly dependent on the membrane-proximal amino acids in the cytoplasmic tail of FcγRIIIAα. Thus, total deletion of the cytoplasmic tail of FcγRIIIAα results in a severely impaired tyrosine phosphorylation of phospholipase C-γl, zap, and syk and rise in intracellular free Ca2+ following receptor ligation with specific anti- CD16 monoclonal antibody or Ig-anti-Ig complexes, suggesting that FcγRIIIAα-ζ association per se is not sufficient to establish the signal function of FcγRIIIA. In conclusion, the present findings demonstrate that the most membrane-proximal amino acids of the FcγRIIIAα cytoplasmic tail play a critical role in ligand-induced signal transduction by the FcγRIIIAα-ζ complex.