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Division of Haematology, Hanson Centre for Cancer Research, IMVS, Adelaide, South Australia
Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) is a
newly assigned member of the Ig immunoreceptor tyrosine-based
inhibitory motif superfamily, and its functional role is suggested to
be an inhibitory receptor that modulates immunoreceptor tyrosine-based
activation motif-dependent signaling cascades. To test whether PECAM-1
is capable of delivering inhibitory signals in B cells and the
functional requirement of protein-tyrosine phosphatases (PTPs) for this
inhibitory signaling, we generated chimeric Fc
RIIB1-PECAM-1
receptors containing the extracellular and transmembrane portions of
murine FcRIIB1 and the cytoplasmic domain of human PECAM-1. These
chimeric receptors were stably expressed in chicken DT40 B cells either
as wild-type or mutant cells deficient in SHP-1-/-,
SHP-2-/-, SHIP-/-, or
SHP-1/2-/- and then assessed for their ability to inhibit
B cell Ag receptor (BCR) signaling. Coligation of wild-type
FcRIIB1-PECAM-1 with BCR resulted in inhibition of intracellular
calcium release, suggesting that the cytoplasmic domain of PECAM-1 is
capable of delivering an inhibitory signal that blocks BCR-mediated
activation. This PECAM-1-mediated inhibitory signaling correlated with
tyrosine phosphorylation of the FcRIIB1-PECAM-1 chimera, recruitment
of SHP-1 and SHP-2 PTPs by the phosphorylated chimera, and attenuation
of calcium mobilization responses. Mutational analysis of the two
tyrosine residues, 663 and 686, constituting the immunoreceptor
tyrosine-based inhibitory motifs in PECAM-1 revealed that both tyrosine
residues play a crucial role in the inhibitory signal. Functional
analysis of various PTP-deficient DT40 B cell lines stably expressing
wild-type chimeric FcRIIB1-PECAM-1 receptor indicated that
cytoplasmic Src homology 2-domain-containing phosphatases, SHP-1 and
SHP-2, were both necessary and sufficient to deliver inhibitory
negative regulation upon coligation of BCR complex with inhibitory
receptor.
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