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https://hdl.handle.net/2440/9612
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Type: | Journal article |
Title: | Src homology 2 domain-containing protein-tyrosine phosphatases, SHP-1 and SHP-2, are required for platelet endothelial cell adhesion molecule-1/CD31-mediated inhibitory signaling |
Author: | Henshall, T. Jones, K. Wilkinson, R. Jackson, D. |
Citation: | Journal of Immunology, 2001; 166(5):3098-3106 |
Publisher: | Amer Assoc Immunologists |
Issue Date: | 2001 |
ISSN: | 0022-1767 1550-6606 |
Abstract: | 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 gamma RIIB1-PECAM-1 receptors containing the extracellular and transmembrane portions of murine Fc gamma RIIB1 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 Fc gamma RIIB1-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 Fc gamma RIIB1-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 Fc gamma RIIB1-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. |
Keywords: | Animals Humans Mice B-Lymphocytes Cell Line Cytoplasm Tyrosine Intracellular Signaling Peptides and Proteins Antigens, CD31 Recombinant Fusion Proteins Signal Transduction Lymphocyte Activation Consensus Sequence Protein Structure, Tertiary src Homology Domains Down-Regulation Amino Acid Motifs Protein Tyrosine Phosphatases Protein Tyrosine Phosphatase, Non-Receptor Type 6 Protein Tyrosine Phosphatase, Non-Receptor Type 11 SH2 Domain-Containing Protein Tyrosine Phosphatases Receptors, IgG Chickens |
DOI: | 10.4049/jimmunol.166.5.3098 |
Published version: | http://dx.doi.org/10.4049/jimmunol.166.5.3098 |
Appears in Collections: | Aurora harvest Medicine publications |
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