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Mechanisms of Activation of Receptor Tyrosine Kinases: Monomers or Dimers
Cells 2014, 3(2), 363-385; doi:10.3390/cells3020363

Endosome-to-Plasma Membrane Recycling of VEGFR2 Receptor Tyrosine Kinase Regulates Endothelial Function and Blood Vessel Formation

1, 1, 2, 1, 2, 3, 1, 2 and 1,*
1 Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, UK 2 Centre for Cardiovascular Biology and Medicine, The Rayne Institute, University College London, UK 3 School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK
* Author to whom correspondence should be addressed.
Received: 2 December 2013 / Revised: 4 March 2014 / Accepted: 17 March 2014 / Published: 29 April 2014
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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Rab GTPases are implicated in endosome-to-plasma membrane recycling, but how such membrane traffic regulators control vascular endothelial growth factor receptor 2 (VEGFR2/KDR) dynamics and function are not well understood. Here, we evaluated two different recycling Rab GTPases, Rab4a and Rab11a, in regulating endothelial VEGFR2 trafficking and signalling with implications for endothelial cell migration, proliferation and angiogenesis. In primary endothelial cells, VEGFR2 displays co-localisation with Rab4a, but not Rab11a GTPase, on early endosomes. Expression of a guanosine diphosphate (GDP)-bound Rab4a S22N mutant caused increased VEGFR2 accumulation in endosomes. TfR and VEGFR2 exhibited differences in endosome-to-plasma membrane recycling in the presence of chloroquine. Depletion of Rab4a, but not Rab11a, levels stimulated VEGF-A-dependent intracellular signalling. However, depletion of either Rab4a or Rab11a levels inhibited VEGF-A-stimulated endothelial cell migration. Interestingly, depletion of Rab4a levels stimulated VEGF-A-regulated endothelial cell proliferation. Rab4a and Rab11a were also both required for endothelial tubulogenesis. Evaluation of a transgenic zebrafish model showed that both Rab4 and Rab11a are functionally required for blood vessel formation and animal viability. Rab-dependent endosome-to-plasma membrane recycling of VEGFR2 is important for intracellular signalling, cell migration and proliferation during angiogenesis.
Keywords: endothelial; VEGF-A; VEGFR2; Rab4a; Rab11a; signalling; angiogenesis endothelial; VEGF-A; VEGFR2; Rab4a; Rab11a; signalling; angiogenesis
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Jopling, H.M.; Odell, A.F.; Pellet-Many, C.; Latham, A.M.; Frankel, P.; Sivaprasadarao, A.; Walker, J.H.; Zachary, I.C.; Ponnambalam, S. Endosome-to-Plasma Membrane Recycling of VEGFR2 Receptor Tyrosine Kinase Regulates Endothelial Function and Blood Vessel Formation. Cells 2014, 3, 363-385.

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