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Dynamic alterations in decoy VEGF receptor-1 stability regulate angiogenesis

Author

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  • Joshua M. Boucher

    (University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
    Present address: The Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA)

  • Ryan P. Clark

    (University of North Carolina at Chapel Hill)

  • Diana C. Chong

    (Genetics and Molecular Biology Curriculum, University of North Carolina at Chapel Hill)

  • Kathryn M. Citrin

    (University of North Carolina at Chapel Hill)

  • Lyndsay A. Wylie

    (Genetics and Molecular Biology Curriculum, University of North Carolina at Chapel Hill)

  • Victoria L. Bautch

    (University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
    Genetics and Molecular Biology Curriculum, University of North Carolina at Chapel Hill
    McAllister Heart Institute, University of North Carolina at Chapel Hill)

Abstract

Blood vessel expansion is driven by sprouting angiogenesis of endothelial cells, and is essential for development, wound healing and disease. Membrane-localized vascular endothelial growth factor receptor-1 (mVEGFR1) is an endothelial cell-intrinsic decoy receptor that negatively modulates blood vessel morphogenesis. Here we show that dynamic regulation of mVEGFR1 stability and turnover in blood vessels impacts angiogenesis. mVEGFR1 is highly stable and constitutively internalizes from the plasma membrane. Post-translational palmitoylation of mVEGFR1 is a binary stabilization switch, and ligand engagement leads to depalmitoylation and lysosomal degradation. Trafficking of palmitoylation enzymes via Rab27a regulates mVEGFR1 stability, as reduced levels of Rab27a impaired palmitoylation of mVEGFR1, decreased its stability, and elevated blood vessel sprouting and in vivo angiogenesis. These findings identify a regulatory axis affecting blood vessel morphogenesis that highlights exquisite post-translational regulation of mVEGFR1 in its role as a molecular rheostat.

Suggested Citation

  • Joshua M. Boucher & Ryan P. Clark & Diana C. Chong & Kathryn M. Citrin & Lyndsay A. Wylie & Victoria L. Bautch, 2017. "Dynamic alterations in decoy VEGF receptor-1 stability regulate angiogenesis," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15699
    DOI: 10.1038/ncomms15699
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