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Published online 8 January 2001. doi:10.1083/jcb.152.1.65
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© The Rockefeller University Press, 0021-9525/2001//65 $5.00
The Journal of Cell Biology, Volume 152, Number 1, , 2001 65-74

Original Article

Integrin Activation by Regulated Dimerization and Oligomerization of Platelet Endothelial Cell Adhesion Molecule (Pecam)-1 from within the Cell



Tieming Zhaoa,b and Peter J. Newmana,b,c

a Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin 53201
b Department of Cellular Biology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
c Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
Blood Research Institute, The Blood Center of Southeastern Wisconsin, P.O. Box 2178, Milwaukee, WI 53201.(414) 937-6284(414) 937-6237

pjnewman{at}bcsew.edu

Platelet endothelial cell adhesion molecule (PECAM)-1 is a 130-kD transmembrane glycoprotein having six Ig homology domains within its extracellular domain and an immunoreceptor tyrosine–based inhibitory motif within its cytoplasmic domain. Previous studies have shown that addition of bivalent anti–PECAM-1 mAbs to the surface of T cells, natural killer cells, neutrophils, or platelets result in increased cell adhesion to immobilized integrin ligands. However, the mechanism by which this occurs is not clear, and it is possible that anti–PECAM-1 mAbs elicit this effect by simply sequestering PECAM-1, via antibody-induced patching and capping, away from stimulatory receptors that it normally regulates. To determine whether dimerization or oligomerization of PECAM-1 directly initiates signal transduction pathways that affect integrin function in an antibody-independent manner, stable human embryonic kidney-293 cell lines were produced that expressed chimeric PECAM-1 cDNAs containing one or two FK506-binding protein (FKBP) domains at their COOH terminus. Controlled dimerization initiated by addition of the bivalent, membrane-permeable FKBP dimerizer, AP1510, nearly doubled homophilic binding capacity, whereas AP1510-induced oligomers favored cis PECAM-1/PECAM-1 associations within the plane of the plasma membrane at the expense of trans homophilic adhesion. Importantly, AP1510-induced oligomerization resulted in a marked increase in both adherence and spreading of PECAM/FKBP-2–transfected cells on immobilized fibronectin, a reaction that was mediated by the integrin {alpha}5β1. These data demonstrate that signals required for integrin activation can be elicited by clustering of PECAM-1 from inside the cell, and suggest that a dynamic equilibrium between PECAM-1 monomers, dimers, and oligomers may control cellular activation signals that influence the adhesive properties of vascular cells that express this novel member of the immunoreceptor tyrosine–based inhibitory motif family of regulatory receptors.

Key Words: PECAM-1 • integrins • FKBP • dimerization • signal transduction

© 2001 The Rockefeller University Press

Abbreviations used in this paper: BS3, bis(sulfosuccinikidyl) suberate; DTSSP, dithiobis(sulfosuccinimidylpropionate); FKBP, FK506-binding protein; HEK, human embryonic kidney; HEL, human erythroleukemia; ITIM, immunoreceptor tyrosine–based inhibitory motif; PECAM-1, platelet endothelial cell adhesion molecule-1.


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