title: VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation.
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.
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjölds v. 20, 751 85 Uppsala, Sweden.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hayashi
authors.forename: Arindam
authors.initials: A
authors.lastname: Majumdar
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Li
authors.forename: Jeremy
authors.initials: J
authors.lastname: Adler
authors.forename: Zuyue
authors.initials: Z
authors.lastname: Sun
authors.forename: Simona
authors.initials: S
authors.lastname: Vertuani
authors.forename: Carina
authors.initials: C
authors.lastname: Hellberg
authors.forename: Sofie
authors.initials: S
authors.lastname: Mellberg
authors.forename: Sina
authors.initials: S
authors.lastname: Koch
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.forename: Heinz-Georg
authors.initials: HG
authors.lastname: Belting
authors.forename: Markus
authors.initials: M
authors.lastname: Affolter
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: Lars
authors.initials: L
authors.lastname: Holmgren
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
mesh_terms: D000818:Animals; D016764:Cell Polarity; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D007365:Intercellular Junctions; D051379:Mice; D010766:Phosphorylation; D042787:Receptor, TIE-2 / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
chemical_list: D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3