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    Protein kinase D up-regulates transcription of VEGF receptor-2 in endothelial cells by suppressing nuclear localization of the transcription factor AP2β

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    Final PDF_09042019.pdf
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    Description:
    Final Accepted Manuscript
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    Author
    Wang, Ying
    Hoeppner, Luke H.
    Angom, Ramcharan Singh
    Wang, Enfeng
    Dutta, Shamit
    Doeppler, Heike R.
    Wang, Fei
    Shen, Tao
    Scarisbrick, Isobel A.
    Guha, Sushovan
    Storz, Peter
    Bhattacharya, Resham
    Mukhopadhyay, Debabrata
    Show allShow less
    Affiliation
    Univ Arizona, Coll Med
    Issue Date
    2019-09-06
    Keywords
    vascular endothelial growth factor (VEGF)
    angiogenesis
    protein kinase D (PKD)
    signal transduction
    endothelial cell
    vascular endothelial growth factor receptor-2
    
    Metadata
    Show full item record
    Publisher
    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
    Citation
    Wang, Y., Hoeppner, L., Angom, R., Wang, E., Dutta, S., & Doeppler, H. et al. (2019). Protein kinase D up-regulates transcription of VEGF receptor-2 in endothelial cells by suppressing nuclear localization of the transcription factor AP2β. Journal Of Biological Chemistry, 294(43), 15759-15767. doi: 10.1074/jbc.ra119.010152
    Journal
    JOURNAL OF BIOLOGICAL CHEMISTRY
    Rights
    Copyright © 2019 Wang et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Vascular endothelial growth factor A (VEGF) signals primarily through its cognate receptor VEGF receptor-2 (VEGFR-2) to control vasculogenesis and angiogenesis, key physiological processes in cardiovascular disease and cancer. In human umbilical vein endothelial cells (HUVECs), knockdown of protein kinase D-1 (PKD1) or PKD2 down-regulates VEGFR-2 expression and inhibits VEGF-induced cell proliferation and migration. However, how PKD regulates VEGF signaling is unclear. Previous bioinformatics analyses have identified binding sites for the transcription factor activating enhancer-binding protein 2 (AP2) in the VEGFR-2 promoter. Using ChIP analyses, here we found that PKD knockdown in HUVECs increases binding of AP2β to the VEGFR-2 promoter. Luciferase reporter assays with serial deletions of AP2-binding sites within the VEGFR-2 promoter revealed that its transcriptional activity negatively correlates with the number of these sites. Next we demonstrated that AP2β up-regulation decreases VEGFR-2 expression and that loss of AP2β enhances VEGFR-2 expression in HUVECs. In vivo experiments confirmed increased VEGFR-2 immunostaining in the spinal cord of AP2β knockout mouse embryos. Mechanistically, we observed that PKD phosphorylates AP2β at Ser258 and Ser277 and suppresses its nuclear accumulation. Inhibition of PKD activity with a pan-PKD inhibitor increased AP2β nuclear localization, and overexpression of both WT and constitutively active PKD1 or PKD2 reduced AP2β nuclear localization through a Ser258- and Ser277-dependent mechanism. Furthermore, substitution of Ser277 in AP2β increased its binding to the VEGFR-2 promoter. Our findings uncover evidence of a molecular pathway that regulates VEGFR-2 expression, insights that may shed light on the etiology of diseases associated with aberrant VEGF/VEGFR signaling.
    ISSN
    0021-9258
    PubMed ID
    31492751
    DOI
    10.1074/jbc.ra119.010152
    Version
    Final accepted manuscript
    Sponsors
    NHLBI, National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [HL140411]; NCI, National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA78383-20, CA187035, CA200572]; Florida Department of Health Cancer Research Chair Fund Florida Grant [3J-02]; American Heart AssociationAmerican Heart Association [13POST14510025, 19CDA34700013]; Mayo Clinic Ted and Loretta Rogers Cardiovascular Career Development Award Honoring Hugh C. Smith
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.ra119.010152
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