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RIIB1-Effector Interactions and Inhibitory Functions1
Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, and Department of Immunology, University of Colorado Health Science Center, Denver, CO 80206
Coaggregation of Fc
RIIB1 with B cell Ag receptors (BCR) leads to
inhibition of BCR-mediated signaling via recruitment of Src homology
domain 2 (SH2)-containing phosphatases. In vitro peptide binding
experiments using phosphotyrosine-containing sequences derived from the
immunoreceptor tyrosine-based inhibitory motif (ITIM) known to mediate
FcRIIB1 effects suggest that the receptor uses SH2-containing
inositol phophatase (SHIP) and SH2-containing phophotyrosine
phosphatase (SHP)-1, as well as SHP-2 as effectors. In contrast,
coimmunoprecipitation studies of receptor-effector associations suggest
that the predominant FcRIIB1 effector protein is SHIP. However,
biologically significant interactions may be lost in such studies if
reactants’ dissociation rates (Kd) are
high. Thus, it is unclear to what extent these assays reflect the
relative recruitment of SHIP, SHP-1, and SHP-2 to the receptor in vivo.
As an alternative approach to this question, we have studied the
effects of ectopically expressed SHIP, SHP-1, or SHP-2 SH2-containing
decoy proteins on FcRIIB1 signaling. Results demonstrate the SHIP is
the predominant intracellular ligand for the phosphorylated FcRIIB1
ITIM, although the SHP-2 decoy exhibits some ability to bind FcRIIB1
and block Fc receptor function. The SHIP SH2, while not affecting
FcRIIB1 tyrosyl phosphorylation, blocks receptor-mediated
recruitment of SHIP, SHIP phosphorylation, recruitment of p52 Shc,
phosphatidylinositol 3,4,5-trisphosphate hydrolysis, inhibition of
mitogen-activated protein kinase activation, and, albeit more modestly,
FcRIIB1 inhibition of Ca2+ mobilization. Taken together,
results implicate ITIM interactions with SHIP as a major mechanism of
FcRIIB1-mediated inhibitory signaling.
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