Platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) is expressed on the surface of endothelial cells (EC) and leukocytes. PECAM-1 plays an important role in endothelial-leukocyte and endothelial-endothelial cell-cell interactions. The anti-PECAM-1 antibody-mediated blockade of these interactions inhibits transendothelial migration (TEM) of leukocytes and angiogenesis. PECAM-1 may accommodate these processes through the regulation of cell adhesive and migratory mechanisms. How PECAM-1 regulates these dynamic processes remain unknown. Here we show that PECAM-1 transduces outside-in signals, which activate MAPK/ERKs and small GTPases. This occurs through PECAM-1-mediated formation of intracellular-signaling complexes, Shc/Grb2/SOS1 and/or Crkl/C3G, which is initiated by PECAM-1 engagement on the surface of leukocytes and/or EC. Src, SHP2, and alternative PECAM-1 pre-mRNA splicing play a regulatory role in these signaling events. Our findings reveal that PECAM-1 engagement on the cell surface can transduce "outside-in" signals and activate MAPK/ERKs and small GTPases, impacting both cadherin-mediated cell-cell and integrin-mediated cell-matrix interactions. Thus, we propose PECAM-1 is an important mediator of vascular barrier and regulator of leukocyte and EC adhesion and migration.
Copyright 2006 Wiley-Liss, Inc.