PECAM-1 engagement counteracts ICAM-1-induced signaling in brain vascular endothelial cells.
Interactions between leukocytes and vascular endothelial cells are mediated by a complex set of membrane adhesion molecules which transduce bi-directional signals in both cell types. Endothelium of the cerebral blood vessels, which constitute the blood-brain barrier, strictly controls adhesion and trafficking of leukocytes into the brain. Investigating signaling pathways triggered by the engagement of adhesion molecules expressed on brain endothelial cells, we previously documented the role of ICAM-1 in activation of the tyrosine phosphorylation of several actin-binding proteins and subsequent rearrangements of the actin cytoskeleton. In the present study, we show that, whereas PECAM-1 is known to control positively the trans-endothelial migration of leukocytes via homophilic interactions between leukocytes and endothelial cells, PECAM-1 engagement on brain endothelial surface unexpectedly counteracts the ICAM-1-induced tyrosine phosphorylation of cortactin and rearrangements of the actin cytoskeleton. We present evidence that the PECAM-1-associated tyrosine phosphatase SHP-2 is required for ICAM-1 signaling, suggesting that its activity might crucially contribute to the regulation of ICAM-1 signaling by PECAM-1. Our findings reveal a novel activity for PECAM-1 which, by counteracting ICAM-1-induced activation, could directly contribute to limit activation and maintain integrity of brain vascular endothelium.
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Jean-Pierre
JP
Couty
Christine
C
Rampon
Mathilde
M
Leveque
Marie-Pierre
MP
Laran-Chich
Sandrine
S
Bourdoulous
John
J
Greenwood
Pierre-Olivier
PO
Couraud
D000818:Animals; D000911:Antibodies, Monoclonal; D001812:Blood-Brain Barrier / Q000502:physiology; D015153:Blotting, Western; D051356:Cortactin / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047468:Immunoprecipitation; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000911:Antibodies, Monoclonal; D051356:Cortactin; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D017027:Protein Tyrosine Phosphatases; D020742:rhoA GTP-Binding Protein