Abstract
Angiogenesis requires concomitant remodeling of cell junctions and migration, as exemplified by recent observations of extensive endothelial cell movement along growing blood vessels. We report that a protein complex that regulates cell junctions is required for VEGF-driven directional migration and for angiogenesis in vivo. The complex consists of RhoA and Syx, a RhoA guanine exchange factor cross-linked by the Crumbs polarity protein Mupp1 to angiomotin, a phosphatidylinositol-binding protein. The Syx-associated complex translocates to the leading edge of migrating cells by membrane trafficking that requires the tight junction recycling GTPase Rab13. In turn, Rab13 associates with Grb2, targeting Syx and RhoA to Tyr(1175)-phosphorylated VEGFR2 at the leading edge. Rab13 knockdown in zebrafish impeded sprouting of intersegmental vessels and diminished the directionality of their tip cells. These results indicate that endothelial cell mobility in sprouting vessels is facilitated by shuttling the same protein complex from disassembling junctions to the leading edges of cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Movement / physiology*
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Endothelial Cells / cytology
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Endothelial Cells / metabolism*
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GRB2 Adaptor Protein / genetics
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GRB2 Adaptor Protein / metabolism
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism
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Membrane Proteins
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Mice
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Mice, Knockout
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Neovascularization, Physiologic / physiology*
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Phosphorylation / physiology
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Tight Junctions / genetics
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Tight Junctions / metabolism
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Zebrafish / embryology
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Zebrafish / genetics
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rab GTP-Binding Proteins / genetics
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rab GTP-Binding Proteins / metabolism*
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rho GTP-Binding Proteins / genetics
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rho GTP-Binding Proteins / metabolism*
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rhoA GTP-Binding Protein
Substances
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Carrier Proteins
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GRB2 Adaptor Protein
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Grb2 protein, mouse
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Guanine Nucleotide Exchange Factors
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Membrane Proteins
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Mpdz protein, mouse
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Syx protein, mouse
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Vascular Endothelial Growth Factor Receptor-2
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Rab13 protein, mouse
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RhoA protein, mouse
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rab GTP-Binding Proteins
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein