Spatial regulation of VEGF receptor endocytosis in angiogenesis.
Activities as diverse as migration, proliferation and patterning occur simultaneously and in a coordinated fashion during tissue morphogenesis. In the growing vasculature, the formation of motile, invasive and filopodia-carrying endothelial sprouts is balanced with the stabilization of blood-transporting vessels. Here, we show that sprouting endothelial cells in the retina have high rates of VEGF uptake, VEGF receptor endocytosis and turnover. These internalization processes are opposed by atypical protein kinase C activity in more stable and mature vessels. aPKC phosphorylates Dab2, a clathrin-associated sorting protein that, together with the transmembrane protein ephrin-B2 and the cell polarity regulator PAR-3, enables VEGF receptor endocytosis and downstream signal transduction. Accordingly, VEGF receptor internalization and the angiogenic growth of vascular beds are defective in loss-of-function mice lacking key components of this regulatory pathway. Our work uncovers how vessel growth is dynamically controlled by local VEGF receptor endocytosis and the activity of cell polarity proteins.
Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Muenster, Faculty of Medicine, D-48149 Muenster, Germany. mnakaya@gwdg.de
Masanori
M
Nakayama
Akiko
A
Nakayama
Max
M
van Lessen
Hiroyuki
H
Yamamoto
Sarah
S
Hoffmann
Hannes C A
HC
Drexler
Norimichi
N
Itoh
Tomonori
T
Hirose
Georg
G
Breier
Dietmar
D
Vestweber
Jonathan A
JA
Cooper
Shigeo
S
Ohno
Kozo
K
Kaibuchi
Ralf H
RH
Adams
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004705:Endocytosis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D036388:Ephrin-B2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; C478773:Dab2 protein, mouse; D036388:Ephrin-B2; C115084:Pard3 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D040262:Receptors, Vascular Endothelial Growth Factor; C115015:PKC-3 protein; D011493:Protein Kinase C