Platelet endothelial cell adhesion molecule-1 modulates endothelial cell motility through the small G-protein Rho.
Platelet endothelial cell adhesion molecule-1 (PECAM-1), an immunoglobulin family vascular adhesion molecule, is involved in endothelial cell migration and angiogenesis (1, 2). We found that endothelial cells lacking PECAM-1 exhibit increased single cell motility and extension formation but poor wound healing migration, reminiscent of cells in which Rho activity has been suppressed by overexpressing a GTPase-activating protein (3). The ability of PECAM-1 to restore wound healing migration to PECAM-1-deficient cells was independent of its extracellular domain or signaling via its immunoreceptor tyrosine-based inhibitory motif. PECAM-1-deficient endothelial cells had a selective defect in RhoGTP loading, and inhibition of Rho activity mimicked the PECAM-1-deficient phenotype of increased chemokinetic single cell motility at the expense of coordinated wound healing migration. The wound healing advantage of PECAM-1-positive endothelial cells was not only Rho mediated but pertussis toxin inhibitable, characteristic of migration mediated by heterotrimeric G-protein-linked seven-transmembrane receptor signaling such as signaling in response to the serum sphingolipid sphingosine-1-phosphate (S1P) (4, 5). Indeed, we found that the wound healing defect of PECAM-1 null endothelial cells is minimized in sphingolipid-depleted media; moreover, PECAM-1 null endothelial cells fail to increase their migration in response to S1P. We have also found that PECAM-1 localizes to rafts and that in its absence heterotrimeric G-protein components are differentially recruited to rafts, providing a potential mechanism for PECAM-1-mediated coordination of S1P signaling. PECAM-1 may thus support the effective S1P/RhoGTP signaling required for wound healing endothelial migration by allowing for the spatially directed, coordinated activation of Galpha signaling pathways.
Gratzinger
Dita
D
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Canosa
Sandra
S
Engelhardt
Britta
B
Madri
Joseph A
JA
D000818:Animals; D002633:Chemotaxis; D004727:Endothelium / Q000166:cytology / Q000502:physiology*; D017353:Gene Deletion; D008246:Lysophospholipids; D021962:Membrane Microdomains / Q000737:chemistry; D051379:Mice; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D008246:Lysophospholipids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C060506:sphingosine 1-phosphate; D020741:rho GTP-Binding Proteins; D013110:Sphingosine