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(Received for publication, October 2, 1996, and in revised form, January 7, 1997)
,
,
and§
From the Platelet/endothelial cell adhesion
molecule-1 (PECAM-1) is a homophilic adhesion receptor that mediates
leukocyte/endothelial cell interactions that take place during
transendothelial migration. Recent reports have shown that the binding
of certain anti-PECAM-1 antibodies results in up-regulation of integrin
function on the surface of leukocytes and platelets, suggesting that
PECAM-1 may be capable of transmitting information into the cell
following its engagement. PECAM-1 isolated from resting or activated
but nonaggregated platelets was phosphorylated predominantly on serine residues; however, PECAM-1 derived from activated,
aggregated platelets was strongly phosphorylated on
tyrosine. Synthetic tyrosine-phosphorylated peptides derived from five
different regions within the cytoplasmic domain of PECAM-1 were
screened for their ability to associate with cytoplasmic signaling
molecules. The protein-tyrosine phosphatase SHP-2 was found to interact
specifically with two different PECAM-1 phosphopeptides containing
highly conserved phosphatase-binding motifs on PECAM-1 with the
sequences VQpY663TEV and TVpY686SEV. More
important, SHP-2 bound not only PECAM-1 phosphopeptides, but also
became associated with full-length cellular PECAM-1 during the platelet
aggregation process, and this interaction was mediated by the
amino-terminal Src homology 2 domains of the phosphatase. Since SHP-2
normally serves as a positive regulator of signal transduction, its
association with activated PECAM-1 suggests a number of potential
mechanisms by which PECAM-1 engagement might be coupled to integrin
activation in vascular cells.
Blood Research Institute, Blood Center of
Southeastern Wisconsin, Milwaukee, Wisconsin 53233-2121 and the
§ Departments of Cellular Biology and Pharmacology, Medical
College of Wisconsin, Milwaukee, Wisconsin 53226
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G. S. Duncan, D. P. Andrew, H. Takimoto, S. A. Kaufman, H. Yoshida, J. Spellberg, J. Luis de la Pompa, A. Elia, A. Wakeham, B. Karan-Tamir, et al. Genetic Evidence for Functional Redundancy of Platelet/Endothelial Cell Adhesion Molecule-1 (PECAM-1): CD31-Deficient Mice Reveal PECAM-1-Dependent and PECAM-1-Independent Functions J. Immunol., March 1, 1999; 162(5): 3022 - 3030. [Abstract] [Full Text] [PDF]
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