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Receptor IIA and Fc Receptor IIIB Signaling Pathways in Human Neutrophils1
Departments of
*
Biochemistry and
Physiology and Biophysics, and
Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029
Human neutrophils (PMNs) express two receptors for the Fc domain of
IgG: the transmembrane Fc
RIIA, whose cytosolic sequence contains an
immunoreceptor tyrosine-based activation motif, and the GPI-anchored
FcRIIIB. Cross-linking of FcRIIIB induces cell activation, but
the mechanism is still uncertain. We have used mAbs to cross-link
selectively each of the two receptors and to assess their signaling
phenotypes and functional relation. Cross-linking of FcRIIIB induces
intracellular Ca2+ release and receptor capping. The
Ca2+ response is blocked by wortmannin and by
N,N-dimethylsphingosine, inhibitors of
phosphatidylinositol 3-kinase and sphingosine kinase, respectively.
Identical dose-response curves are obtained for the Ca2+
release stimulated by cross-linking FcRIIA, implicating these two
enzymes in a common signaling pathway. Wortmannin also inhibits capping
of both receptors, but not receptor endocytosis. Fluorescence
microscopy in double-labeled PMNs demonstrates that FcRIIA
colocalizes with cross-linked FcRIIIB. The signaling phenotypes of
the two receptors diverge only under frustrated phagocytosis
conditions, where FcRIIIB bound to substrate-immobilized Ab does not
elicit cell spreading. We propose that FcRIIIB signaling is
conducted by molecules of FcRIIA that are recruited to protein/lipid
domains induced by clustered FcRIIIB and, thus, are brought into
juxtaposition for immunoreceptor tyrosine-based activation motif
phosphorylation and activation of PMNs.
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