A Heat-Shock Protein Axis Regulates VEGFR2 Proteolysis, Blood Vessel Development and Repair
Open Access
- 6 November 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (11), e48539
- https://doi.org/10.1371/journal.pone.0048539
Abstract
Vascular endothelial growth factor A (VEGF-A) binds to the VEGFR2 receptor tyrosine kinase, regulating endothelial function, vascular physiology and angiogenesis. However, the mechanism underlying VEGFR2 turnover and degradation in this response is unclear. Here, we tested a role for heat-shock proteins in regulating the presentation of VEGFR2 to a degradative pathway. Pharmacological inhibition of HSP90 stimulated VEGFR2 degradation in primary endothelial cells and blocked VEGF-A-stimulated intracellular signaling via VEGFR2. HSP90 inhibition stimulated the formation of a VEGFR2-HSP70 complex. Clathrin-mediated VEGFR2 endocytosis is required for this HSP-linked degradative pathway for targeting VEGFR2 to the endosome-lysosome system. HSP90 perturbation selectively inhibited VEGF-A-stimulated human endothelial cell migration in vitro. A mouse femoral artery model showed that HSP90 inhibition also blocked blood vessel repair in vivo consistent with decreased endothelial regeneration. Depletion of either HSP70 or HSP90 caused defects in blood vessel formation in a transgenic zebrafish model. We conclude that perturbation of the HSP70-HSP90 heat-shock protein axis stimulates degradation of endothelial VEGFR2 and modulates VEGF-A-stimulated intracellular signaling, endothelial cell migration, blood vessel development and repair.Keywords
This publication has 51 references indexed in Scilit:
- Molecular mechanisms and clinical applications of angiogenesisNature, 2011
- PEST Motif Serine and Tyrosine Phosphorylation Controls Vascular Endothelial Growth Factor Receptor 2 Stability and DownregulationMolecular and Cellular Biology, 2011
- Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligaseProceedings of the National Academy of Sciences, 2009
- VEGF-A splicing: the key to anti-angiogenic therapeutics?Nature Reviews Cancer, 2008
- Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancerHistochemistry and Cell Biology, 2008
- Src-mediated Phosphorylation of Hsp90 in Response to Vascular Endothelial Growth Factor (VEGF) Is Required for VEGF Receptor-2 Signaling to Endothelial NO SynthaseMolecular Biology of the Cell, 2007
- Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-TerminusMolecular Biology of the Cell, 2007
- A critical role for the E3-ligase activity of c-Cbl in VEGFR-2-mediated PLCγ1 activation and angiogenesisProceedings of the National Academy of Sciences, 2007
- Phosphorylation of Focal Adhesion Kinase (FAK) on Ser732 Is Induced by Rho-dependent Kinase and Is Essential for Proline-rich Tyrosine Kinase-2–mediated Phosphorylation of FAK on Tyr407 in Response to Vascular Endothelial Growth FactorMolecular Biology of the Cell, 2006
- Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesisExperimental Cell Research, 2006