Spatial regulation of VEGF receptor endocytosis in angiogenesis

Masanori Nakayama, Akiko Nakayama, Max Van Lessen, Hiroyuki Yamamoto, Sarah Hoffmann, Hannes C.A. Drexler, Norimichi Itoh, Tomonori Hirose, Georg Breier, Dietmar Vestweber, Jonathan A. Cooper, Shigeo Ohno, Kozo Kaibuchi, Ralf H. Adams

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)249-260
Number of pages12
JournalNature Cell Biology
Volume15
Issue number3
DOIs
Publication statusPublished - 03-2013

All Science Journal Classification (ASJC) codes

  • Cell Biology

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  • Cite this

    Nakayama, M., Nakayama, A., Van Lessen, M., Yamamoto, H., Hoffmann, S., Drexler, H. C. A., Itoh, N., Hirose, T., Breier, G., Vestweber, D., Cooper, J. A., Ohno, S., Kaibuchi, K., & Adams, R. H. (2013). Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nature Cell Biology, 15(3), 249-260. https://doi.org/10.1038/ncb2679