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

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-Georg Belting, Markus Affolter, Gavin Thurston, Lars Holmgren, Dietmar Vestweber and Lena Claesson-Welsh ()
Additional contact information
Makoto Hayashi: Uppsala University, Genetics and Pathology, Rudbeck Laboratory
Arindam Majumdar: Uppsala University, Genetics and Pathology, Rudbeck Laboratory
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

Nature Communications, 2013, vol. 4, issue 1, 1-15

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2683

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