ARP2/3-mediated junction-associated lamellipodia control VE-cadherin-based cell junction dynamics and maintain monolayer integrity.
Maintenance and remodeling of endothelial cell junctions critically depend on the VE-cadherin/catenin complex and its interaction with the actin filament cytoskeleton. Here we demonstrate that local lack of vascular endothelial (VE)-cadherin at established cell junctions causes actin-driven and actin-related protein 2/3 complex (ARP2/3)-controlled lamellipodia to appear intermittently at those sites. Lamellipodia overlap the VE-cadherin-free adjacent plasma membranes and facilitate formation of new VE-cadherin adhesion sites, which quickly move into the junctions, driving VE-cadherin dynamics and remodeling. Inhibition of the ARP2/3 complex by expression of the N-WASP (V)CA domain or application of two ARP2/3 inhibitors, CK-548 and CK-666, blocks VE-cadherin dynamics and causes intercellular gaps. Furthermore, expression of carboxy-terminal-truncated VE-cadherin increases the number of ARP2/3-controlled lamellipodia, whereas overexpression of wild-type VE-cadherin largely blocks it and decreases cell motility. The data demonstrate a functional interrelationship between VE-cadherin-mediated cell adhesion and actin-driven, ARP2/3-controlled formation of new VE-cadherin adhesion sites via intermittently appearing lamellipodia at established cell junctions. This coordinated mechanism controls VE-cadherin dynamics and cell motility and maintains monolayer integrity, thus potentially being relevant in disease and angiogenesis.
Institute of Anatomy and Vascular Biology, WWU-Münster, 48149 Münster, Germany.
Abdallah
A
Abu Taha
Muna
M
Taha
Jochen
J
Seebach
Hans-J
HJ
Schnittler
D008841:Actin Cytoskeleton / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism*; D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism*; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
D051376:Actin-Related Protein 2-3 Complex; D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5