on May 21, 2009
Published online before print May 21, 2009, doi: 10.1161/ATVBAHA.109.189217
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Submitted on April 16, 2008
Accepted on May 3, 2009
JAM-C Induces Endothelial Cell Permeability Through Its Association and Regulation of 
3 Integrins
Xiaochun Li ;
From the Division of Human Immunology (X.L., M.S., C.N.H.), Hanson Institute, Institute of Medical & Veterinary Science, Adelaide, South Australia; the Department of Pathology (B.P.-L.L., B.A.I.), University of Geneva, Switzerland; UMR891 (M.A.-L.), INSERM, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, France; and the Centenary Institute of Cancer Medicine and Cell Biology, Department of Medicine (Y.L., M.V., J.G.), University of Sydney, Newtown, NSW.
* To whom correspondence should be addressed. E-mail: j.gamble{at}centenary.org.au.
Objectives—The molecular mechanisms regulating vascular permeability are only now being elucidated. The junctional adhesion molecule (JAM) JAM-C has been linked to the induction of vascular permeability. We sought to understand the mechanism whereby JAM-C may disrupt junctional integrity in endothelial cells (ECs).
Methods and Results—We show here that JAM-C alters permeability through modulation of integrin activity. JAM-C overexpression results in an increase in JAM-C at junctions and an increase in permeability. Conversely, knockdown of JAM-C by siRNA results in a reduction in permeability. JAM-C associates with 
v
3 integrin and regulates its localization and activity. JAM-C also inhibits the activation state of the 1 integrin although it does not associate with this integrin. These changes induced on the integrins are mediated through regulation of the small GTPase, Rap1b but not Rap1a. Thrombin, a powerful inductor of vascular leak, causes localization of JAM-C into the junctions, whereas angiopoietin-1, an inhibitor of permeability, prevents JAM-C translocation.
Conclusions—The regulation of EC junctional integrity involves the coordinated and dynamic modification of localization and activity of junctional stabilizers such as the integrin 3 and the destabilizer, JAM-C.
Key words: junctional adhesion molecule C • endothelial permeability • integrin • Rap1b • VE cadherin