Endosome-to-Plasma Membrane Recycling of VEGFR2 Receptor Tyrosine Kinase Regulates Endothelial Function and Blood Vessel Formation
| Autor: | Paul Frankel, Caroline Pellet-Many, Sreenivasan Ponnambalam, Asipu Sivaprasadarao, Antony M. Latham, Helen M. Jopling, John H. Walker, Ian Zachary, Adam F. Odell |
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| Rok vydání: | 2014 |
| Předmět: |
Angiogenesis
Endosome Rab4a Kinase insert domain receptor QD415-436 General Medicine GTPase Biology Article VEGF-A Receptor tyrosine kinase endothelial VEGFR2 Rab11a signalling angiogenesis Cell biology Endothelial stem cell Vascular endothelial growth factor A lcsh:Biology (General) cardiovascular system biology.protein Rab lcsh:QH301-705.5 |
| Zdroj: | Cells, Vol 3, Iss 2, Pp 363-385 (2014) Cells Cells; Volume 3; Issue 2; Pages: 363-385 |
| ISSN: | 2073-4409 |
| DOI: | 10.3390/cells3020363 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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