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VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis.

  • Basagiannis D Institute of Molecular Biology and Biotechnology-Biomedical Research, Foundation for Research and Technology, Ioannina 45110, Greece.
  • Zografou S Institute of Molecular Biology and Biotechnology-Biomedical Research, Foundation for Research and Technology, Ioannina 45110, Greece.
  • Murphy C Institute of Molecular Biology and Biotechnology-Biomedical Research, Foundation for Research and Technology, Ioannina 45110, Greece.
  • Fotsis T Institute of Molecular Biology and Biotechnology-Biomedical Research, Foundation for Research and Technology, Ioannina 45110, Greece.
  • Morbidelli L Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • Ziche M Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • Bleck C Institute of Biochemistry, ETH, Zurich 8093, Switzerland.
  • Mercer J Institute of Biochemistry, ETH, Zurich 8093, Switzerland.
  • Christoforidis S Institute of Molecular Biology and Biotechnology-Biomedical Research, Foundation for Research and Technology, Ioannina 45110, Greece savvas_christoforidis@imbb.forth.gr schristo@uoi.gr.
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  • 2016-09-23
Published in:
  • Journal of cell science. - 2016
Endocytosis
Macropinocytosis
Membrane trafficking
Signalling
VEGF
VEGFR2
Clathrin
Dynamins
Human Umbilical Vein Endothelial Cells
Humans
Models, Biological
Neovascularization, Physiologic
Pinocytosis
Signal Transduction
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
cdc42 GTP-Binding Protein
English Endocytosis plays a crucial role in receptor signalling. VEGFR2 (also known as KDR) and its ligand VEGFA are fundamental in neovascularisation. However, our understanding of the role of endocytosis in VEGFR2 signalling remains limited. Despite the existence of diverse internalisation routes, the only known endocytic pathway for VEGFR2 is the clathrin-mediated pathway. Here, we show that this pathway is the predominant internalisation route for VEGFR2 only in the absence of ligand. Intriguingly, VEGFA induces a new internalisation itinerary for VEGFR2, the pathway of macropinocytosis, which becomes the prevalent endocytic route for the receptor in the presence of ligand, whereas the contribution of the clathrin-mediated route becomes minor. Macropinocytic internalisation of VEGFR2, which mechanistically is mediated through the small GTPase CDC42, takes place through macropinosomes generated at ruffling areas of the membrane. Interestingly, macropinocytosis plays a crucial role in VEGFA-induced signalling, endothelial cell functions in vitro and angiogenesis in vivo, whereas clathrin-mediated endocytosis is not essential for VEGFA signalling. These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGFA-driven internalisation of VEGFR2 through macropinocytosis is essential for endothelial cell signalling and angiogenesis.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/155246
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