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RIIB Inhibition of Fc
RI Signaling1
* Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, CO 80206; and
Molecular Biology Program and Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences, Cornell University, New York, NY 10021
The low-affinity receptor for IgG, Fc
RIIB, is expressed widely
in the immune system and functions to attenuate Ag-induced immune
responses. In mast cells, coaggregation of FcRIIB with the
high-affinity IgE receptor, Fc
RI, leads to inhibition of Ag-induced
degranulation and cytokine production. FcRIIB inhibitory activity
requires a conserved motif within the FcRIIB cytoplasmic domain
termed the immunoreceptor tyrosine-based inhibition motif. When
coaggregated with an activating receptor (e.g., FcRI, B cell Ag
receptor), FcRIIB is rapidly phosphorylated on tyrosine and recruits
the SH2 domain-containing inositol 5-phosphatase (SHIP). However, the
mechanisms by which SHIP mediates FcRIIB inhibitory function in mast
cells remain poorly defined. In this report we demonstrate that
FcRIIB coaggregation with FcRI stimulates enhanced SHIP tyrosine
phosphorylation and association with Shc and
p62dok. Concurrently, enhanced
p62dok tyrosine phosphorylation and association
with RasGAP are observed, suggesting that SHIP may mediate FcRIIB
inhibitory function in mast cells via recruitment of
p62dok and RasGAP. Supporting this hypothesis,
recruitment of p62dok to FcRI is sufficient
to inhibit FcRI-induced calcium mobilization and extracellular
signal-regulated kinase 1/2 activation. Interestingly, both the
amino-terminal pleckstrin homology and phosphotyrosine binding domains
and the carboxyl-terminal proline/tyrosine-rich region of
p62dok can mediate inhibition, suggesting
activation of parallel downstream signaling pathways that converge at
extracellular signal-regulated kinase 1/2 activation. Finally, studies
using gene-ablated mice indicate that p62dok is
dispensable for FcRIIB inhibitory signaling in mast cells. Taken
together, these data suggest a role for p62dok
as a mediator of FcRIIB inhibition of FcRI signal transduction in
mast cells.
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