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

Author:

Basagiannis Dimitris12,Zografou Sofia1,Murphy Carol13,Fotsis Theodore12,Morbidelli Lucia4,Ziche Marina4,Bleck Christopher5,Mercer Jason56,Christoforidis Savvas12ORCID

Affiliation:

1. Institute of Molecular Biology and Biotechnology-Biomedical Research, Foundation for Research and Technology, 45110 Ioannina, Greece

2. Laboratory of Biological Chemistry, Department of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece

3. School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

4. Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy

5. Institute of Biochemistry, ETH Zurich, Switzerland

6. MRC-Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK

Abstract

Endocytosis plays critical role in receptor signalling. VEGFR2 and its ligand VEGFA are fundamental in neovascularization. Yet, our understanding of the role of endocytosis in VEGFR2 signalling remains limited. Despite the existence of diverse internalisation routes, the only known endocytic pathway of VEGFR2 is the clathrin-mediated. Here, we show that this pathway is the predominant internalisation route of VEGFR2 only in the absence of ligand. Intriguingly, VEGF introduces a novel internalisation itinerary for VEGFR2, the pathway of macropinocytosis, which becomes the prevalent endocytic route of the receptor in the presence of ligand, while the route of clathrin becomes minor. Macropinocytic internalisation of VEGFR2, which mechanistically is mediated via the small GTPase CDC42, takes place via macropinosomes generated at ruffling areas of the membrane. Interestingly, macropinocytosis plays critical role in VEGF-induced signalling, endothelial cell functions in vitro and angiogenesis in vivo, while clathrin-mediated endocytosis is not essential for VEGF signalling. These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGF-driven internalisation of VEGFR2 via macropinocytosis is essential for endothelial cell signalling and angiogenesis.

Funder

European Molecular Biology Organization

European Union 6th Framework Programme

European Social Fund and General Secretary for Research and Technology, Greece

Associazione Italiana per la Ricerca sul Cancro

Istituto Toscano Tumori

State Scholarships Foundation, Greece

Publisher

The Company of Biologists

Subject

Cell Biology

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