Journal
JOURNAL OF CELL SCIENCE
Volume 129, Issue 21, Pages 4091-4104Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.188219
Keywords
Endocytosis; Macropinocytosis; Membrane trafficking; Signalling; VEGF; VEGFR2
Categories
Funding
- European Molecular Biology Organization (EMBO) Young Investigator Program
- EU, Sixth Framework Programme (FP6)
- ARISTEIA II
- Heracleitus II
- Synergasia
- KRIPIS
- European Union (European Social Fund, ESF)
- Greek national funds through Ministry of Education, Lifelong Learning and Religious Affairs
- Excellence Program of the State Scholarships Foundation, Greece, IKY-Siemens
- Italian Association for Cancer Research [Associazione Italiana per la Ricerca sul Cancro (AIRC)] [IG10731, IG15443]
- Istituto Toscano Tumori (ITT grant proposal)
- MRC [MC_UU_12018/7] Funding Source: UKRI
- Medical Research Council [MC_UU_12018/7] Funding Source: researchfish
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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 VEGFAinduced 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.
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