PUBLICATION
Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis
- Authors
- Srinivasan, S., Chitalia, V., Meyer, R.D., Hartsough, E., Mehta, M., Harrold, I., Anderson, N., Feng, H., Smith, L.E., Jiang, Y., Costello, C.E., Rahimi, N.
- ID
- ZDB-PUB-150611-8
- Date
- 2015
- Source
- Angiogenesis 18(4): 449-62 (Journal)
- Registered Authors
- Anderson, Nicole M., Feng, Hui, Harrold, Itrat
- Keywords
- Angiogenesis, VEGFR-2, PDCL3, Hypoxia, Protein ubiquitination, N-terminal methionine acetylation, Chaperone protein
- MeSH Terms
-
- Animals
- Carrier Proteins/metabolism*
- Gene Expression Regulation*
- HEK293 Cells
- Human Umbilical Vein Endothelial Cells/metabolism*
- Human Umbilical Vein Endothelial Cells/pathology
- Humans
- Hypoxia/metabolism*
- Hypoxia/pathology
- Mice
- Molecular Chaperones/metabolism*
- Neovascularization, Physiologic*
- Nerve Tissue Proteins/metabolism*
- Protein Folding
- Vascular Endothelial Growth Factor Receptor-2/biosynthesis*
- PubMed
- 26059764 Full text @ Angiogenesis
Citation
Srinivasan, S., Chitalia, V., Meyer, R.D., Hartsough, E., Mehta, M., Harrold, I., Anderson, N., Feng, H., Smith, L.E., Jiang, Y., Costello, C.E., Rahimi, N. (2015) Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. Angiogenesis. 18(4):449-62.
Abstract
Expression and activation of vascular endothelial growth factor receptor 2 (VEGFR-2) by VEGF ligands are the main events in the stimulation of pathological angiogenesis. VEGFR-2 expression is generally low in the healthy adult blood vessels, but its expression is markedly increased in the pathological angiogenesis. In this report, we demonstrate that phosducin-like 3 (PDCL3), a recently identified chaperone protein involved in the regulation of VEGFR-2 expression, is required for angiogenesis in zebrafish and mouse. PDCL3 undergoes N-terminal methionine acetylation, and this modification affects PDCL3 expression and its interaction with VEGFR-2. Expression of PDCL3 is regulated by hypoxia, the known stimulator of angiogenesis. The mutant PDCL3 that is unable to undergo N-terminal methionine acetylation was refractory to the effect of hypoxia. The siRNA-mediated silencing of PDCL3 decreased VEGFR-2 expression resulting in a decrease in VEGF-induced VEGFR-2 phosphorylation, whereas PDCL3 over-expression increased VEGFR-2 protein. Furthermore, we show that PDCL3 protects VEGFR-2 from misfolding and aggregation. The data provide new insights for the chaperone function of PDCL3 in angiogenesis and the roles of hypoxia and N-terminal methionine acetylation in PDCL3 expression and its effect on VEGFR-2.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping