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Blood, 1 June 2001, Vol. 97, No. 11, pp. 3478-3483
IMMUNOBIOLOGY
Cytokine-induced inside-out activation of Fc R
(CD89) is mediated by a single serine residue
(S263) in the intracellular domain of the
receptor
Madelon Bracke,
Jan-Willem
J. Lammers,
Paul J. Coffer, and
Leo Koenderman
From the Department of Pulmonary Diseases, University
Hospital Utrecht, The Netherlands.
Fc receptors play an important role in leukocyte activation and the
modulation of ligand binding ("activation") is a critical point of
regulation. Previous studies demonstrated that the Fc receptor for IgA
(Fc 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 FcRI
activation, cell lines expressing various receptor mutants were
generated. Binding studies indicated that truncation of the C-terminus
of the FcRI resulted in constitutive IgA binding, removing the need
for cytokine stimulation. Furthermore, mutagenesis of a single
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 (S>D) mutation was no longer functional. The role of S263
might be in regulating the interaction with the cytoskeleton, because
disruption of the cytoskeleton results in reduced IgA binding to both
FcRwt and FcR_S>A. In addition, overexpression of a
membrane-targeted intracellular domain of FcR, and the introduction
of cell-permeable CD89 fusion proteins blocked IgA binding, implying a
competition for endogenous proteins. The proposal is made that Fc
receptors are activated by cytokines via an inside-out mechanism
converging at the cytoplasmic tail of these receptors.
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