Angiogenic sprouting requires the fine tuning of endothelial cell cohesion by the Raf-1/Rok-α complex.
Sprouting angiogenesis, crucial for the development of new blood vessels, is a prime example of collective migration in which endothelial cells migrate as a group joined via cadherin-containing adherens junctions (AJ). The actomyosin apparatus is connected to AJ and generates contractile forces, which, depending on their strength and duration, increase or decrease cell cohesion. Thus, appropriate spatiotemporal control of junctional myosin is critical, but the mechanisms underlying it are incompletely understood. We show that Raf-1 is an essential component of this regulatory network and that its ablation impairs endothelial cell cohesion, sprouting, and tumor-induced angiogenesis. Mechanistically, Raf-1 is recruited to VE-cadherin complexes by a mechanism involving the small G protein Rap1 and is required to bring the Rho effector Rok-α to nascent AJs. This Raf-1-mediated fine tuning of Rok-α signaling allows the activation of junctional myosin and the timely maturation of AJ essential for maintaining cell cohesion during sprouting angiogenesis.
Department of Microbiology and Immunobiology, University of Vienna, Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, 1030 Vienna, Austria.
Reiner
R
Wimmer
Botond
B
Cseh
Barbara
B
Maier
Karina
K
Scherrer
Manuela
M
Baccarini
D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability; D002448:Cell Adhesion / Q000502:physiology*; D002450:Cell Communication; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D022001:Focal Adhesions / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
D000205:Actomyosin; D015703:Antigens, CD; D015820:Cadherins; D019908:Proto-Oncogene Proteins c-raf; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D020827:rap1 GTP-Binding Proteins; D054460:rho-Associated Kinases; D000099152:Cadherin 5; C467480:vascular endothelial growth factor A, mouse; C515855:Rock2 protein, mouse