JAM-C induces endothelial cell permeability through its association and regulation of {beta}3 integrins.
OBJECTIVE
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).


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 alphavbeta3 integrin and regulates its localization and activity. JAM-C also inhibits the activation state of the beta(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 beta(3) and the destabilizer, JAM-C.
Li
Xiaochun
X
Centenary Institute of Cancer Medicine and Cell Biology, Locked bag#6, Newtown, NSW, Australia.
Stankovic
Milena
M
Lee
Boris P-L
BP
Aurrand-Lions
Michel
M
Hahn
Chris N
CN
Lu
Ying
Y
Imhof
Beat A
BA
Vadas
Mathew A
MA
Gamble
Jennifer R
JR
D000256:Adenoviridae / Q000235:genetics; D002199:Capillary Permeability / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D002463:Cell Membrane Permeability / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D039661:Integrin beta3 / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics*; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology
D015815:Cell Adhesion Molecules; D039661:Integrin beta3; C448000:JAM3 protein, human; D034741:RNA, Small Interfering