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Department of Pathology, Yale University School of Medicine, New Haven Connecticut 06510, USA
1Correspondence: Department of Pathology, Yale University School of Medicine, 310 Cedar St., P.O. Box 208023, New Haven, CT 06520-8023, USA. E-mail: joseph.madri{at}yale.edu
Shedding of cell surface molecules, including growth factor receptors,
provides a mechanism by which cells regulate signal transduction
events. Here we show that platelet-endothelial cell adhesion molecule
(PECAM)-1 is shed from the endothelial cell surface during apoptosis
and accumulates in the culture medium as a 
100 kDa soluble protein.
The cleavage mediating the shedding is matrix metalloproteinase (MMP)
dependent, as GM6001, a broad-spectrum MMP inhibitor, inhibits PECAM-1
accumulation in the culture medium in a dose-responsive manner. In
addition to the 100 kDa soluble fragment, PECAM-1 cleavage generates
the formation of a truncated (Tr.) 28 kDa molecule, composed of the
transmembrane and the cytoplasmic PECAM-1 domains. Transfections of the
full-length (Fl) and the Tr. PECAM-1 gene constructs into endothelial
and nonendothelial cells were performed. We found 1)
significantly more 
-catenin and SHP-2 bound to the truncated than to
the full-length PECAM-1; 2) stable expression of the
truncated PECAM-1 in SW480 colon carcinoma cells resulted in a dramatic
decrease in cell proliferation, whereas expression of comparable levels
of the full-length PECAM-1 had no effect; 3) the
decrease observed in cell proliferation is due, in part, to an increase
in programmed cell death (apoptosis) and correlated with continuous
caspase 8 cleavage and p38/JNK phosphorylation. These results support
the intimate involvement of PECAM-1 in signal transduction cascades and
also suggest that caspase substrates (e.g., PECAM-1) may possess
distinct and unique functions on cleavage.—Ilan, N., Mohsenin, A.,
Cheung, L., Madri, J. A. PECAM-1 shedding during apoptosis
generates a membrane-anchored truncated molecule with unique signaling
characteristics.
Key Words: platelet-endothelial cell adhesion molecule (CD31) • endothelium • apoptosis • shedding • cleavage
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