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VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation

Author

Listed:
  • Makoto Hayashi

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory)

  • Arindam Majumdar

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory
    Cancer Center Karolinska (CCK), Karolinska Institutet)

  • Xiujuan Li

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory)

  • Jeremy Adler

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory)

  • Zuyue Sun

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory)

  • Simona Vertuani

    (Cancer Center Karolinska (CCK), Karolinska Institutet)

  • Carina Hellberg

    (School of Biosciences, University of Birmingham)

  • Sofie Mellberg

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory)

  • Sina Koch

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory)

  • Anna Dimberg

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory)

  • Gou Young Koh

    (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)

  • Elisabetta Dejana

    (IFOM-IEO Campus Via Adamello)

  • Heinz-Georg Belting

    (Biozentrum der Universität Basel)

  • Markus Affolter

    (Biozentrum der Universität Basel)

  • Gavin Thurston

    (Regeneron Pharmaceuticals Inc)

  • Lars Holmgren

    (Cancer Center Karolinska (CCK), Karolinska Institutet)

  • Dietmar Vestweber

    (Max Planck Institute for Molecular Biomedicine)

  • Lena Claesson-Welsh

    (Uppsala University, Genetics and Pathology, Rudbeck Laboratory)

Abstract

Vascular endothelial growth factor (VEGF) guides the path of new vessel sprouts by inducing VEGF receptor-2 activity in the sprout tip. In the stalk cells of the sprout, VEGF receptor-2 activity is downregulated. Here, we show that VEGF receptor-2 in stalk cells is dephosphorylated by the endothelium-specific vascular endothelial-phosphotyrosine phosphatase (VE-PTP). VE-PTP acts on VEGF receptor-2 located in endothelial junctions indirectly, via the Angiopoietin-1 receptor Tie2. VE-PTP inactivation in mouse embryoid bodies leads to excess VEGF receptor-2 activity in stalk cells, increased tyrosine phosphorylation of VE-cadherin and loss of cell polarity and lumen formation. Vessels in ve-ptp−/− teratomas also show increased VEGF receptor-2 activity and loss of endothelial polarization. Moreover, the zebrafish VE-PTP orthologue ptp-rb is essential for polarization and lumen formation in intersomitic vessels. We conclude that the role of Tie2 in maintenance of vascular quiescence involves VE-PTP-dependent dephosphorylation of VEGF receptor-2, and that VEGF receptor-2 activity regulates VE-cadherin tyrosine phosphorylation, endothelial cell polarity and lumen formation.

Suggested Citation

  • Makoto Hayashi & Arindam Majumdar & Xiujuan Li & Jeremy Adler & Zuyue Sun & Simona Vertuani & Carina Hellberg & Sofie Mellberg & Sina Koch & Anna Dimberg & Gou Young Koh & Elisabetta Dejana & Heinz-Ge, 2013. "VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation," Nature Communications, Nature, vol. 4(1), pages 1-15, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2683
    DOI: 10.1038/ncomms2683
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    Cited by:

    1. Eun-A Kwak & Christopher C. Pan & Aaron Ramonett & Sanjay Kumar & Paola Cruz-Flores & Tasmia Ahmed & Hannah R. Ortiz & Jeffrey J. Lochhead & Nathan A. Ellis & Ghassan Mouneimne & Teodora G. Georgieva , 2022. "βIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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