Cytokine-induced inside-out activation of Fc alpha R (CD89) is mediated bya single serine residue (S263) in the intracellular domain of the receptor

Fc receptors play an important role in leukocyte activation and the modulat ion of ligand binding ("activation") is a critical point of regulation. Pre vious studies demonstrated that the Pc receptor for IgA (Fc alpha RI/CD89) is regulated by cytokine stimulation, switching it to a high-binding state, To investigate the mechanism by which cytokine-induced signal transduction pathways result in Fc alpha RI activation, cell lines expressing various r eceptor mutants were generated. Binding studies indicated that truncation o f the C-terminus of the Fc alpha RI resulted in constitutive IgA binding, r emoving the need for cytokine stimulation. Furthermore, mutagenesis of a si ngle C-terminal serine residue (S263) to alanine (S>A) (single-letter amino acid codes) also resulted in constitutive IgA binding, whereas a serine to aspartate (SID) mutation was no longer functional. The role of S263 might he in regulating the interaction with the cytoskeleton, because disruption of the cytoskeleton results in reduced IgA binding to both Fc alpha Rwt and Fc alphaR_S>A. In addition, overexpression of a membrane-targeted intracel lular domain of Fc alphaR, and the introduction of cell-permeable CD89 fusi on proteins blocked IgA binding, implying a competition for endogenous prot eins. The proposal is made that Pc receptors are activated by cytokines via an inside-out mechanism converging at the cytoplasmic tail of these recept ors, (Blood.2001;97:3478-3483) (C) 2001 by The American Society of Hematolo gy.