PECAM‐1 isoform‐specific activation of MAPK/ERKs and small GTPases: Implications in inflammation and angiogenesis

Abstract 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. J. Cell. Biochem. 98: 451–468, 2006. © 2006 Wiley‐Liss, Inc.