Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK
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SCOPUS
- Title
- Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK
- Authors
- Cho, CH; Lee, CS; Chang, MY; Jang, IH; Kim, SJ; Hwang, IW; Ryu, SH; Lee, CO; Koh, GY
- Date Issued
- 2004-05
- Publisher
- AMER PHYSIOLOGICAL SOC
- Abstract
- To clarify the role of caveolae in VEGF/VEGF receptor-2 (VEGFR-2)-mediated signaling cascades, primary cultured human umbilical vein endothelial cells (HUVECs) were fractionated to isolate caveolae-enriched cell membranes. Interestingly, VEGFR-2, phospholipase D-2 (PLD2), and Ras were enriched in caveolae-enriched fractions. Moreover, VEGF increased PLD activity in a time- and dose-dependent manner in HUVECs, whereas a ligand specific for VEGFR-1 placental growth factor did not change PLD activity. A PLD inhibitor, 1-butanol, almost completely suppressed VEGF-induced ERK phosphorylation and cellular proliferation, whereas the negative control for 1-butanol, 3-butanol, did not produce significant changes. Addition of phosphatidic acid negated the 1-butanol-induced suppression. Pharmacological analyses using several inhibitors indicated that PKC-delta regulates the VEGF-induced activation of PLD/ERK. Thus PLD2 could be involved in MEK/ERK signaling cascades that are induced by the VEGF/VEGFR-2/PKC-delta pathway in endothelial cells. Pretreatment with the cholesterol depletion agent methyl-beta-cyclodextrin (MbetaCD) almost completely disassembled caveolar structures, whereas the addition of cholesterol to MbetaCD-treated cells restored caveolar structures. Pretreatment with MbetaCD largely abolished phosphorylation of MEK/ERK by VEGF, whereas the addition of cholesterol restored VEGF-induced MEK/ERK phosphorylations. These results indicate that intact caveolae are required for the VEGF/VEGFR-2-mediated MEK/ERK signaling cascade.
- Keywords
- caveolin-1; protein kinase C-delta; signaling; vascular endothelial growth factor; phospholipase D; PROTEIN-KINASE-C; SIGNAL-TRANSDUCTION PATHWAY; CELL GROWTH-FACTOR; PHOSPHOLIPASE-D; PLASMA-MEMBRANE; DNA-SYNTHESIS; LIPID RAFTS; ACTIVATION; CHOLESTEROL; TRANSPORT
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/17985
- DOI
- 10.1152/ajpheart.00786.2003
- ISSN
- 0363-6135
- Article Type
- Article
- Citation
- AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, vol. 286, no. 5, page. H1881 - H1888, 2004-05
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