Abstract
F-BAR proteins are multivalent adaptors that link plasma membrane and cytoskeleton and coordinate cellular processes such as membrane protrusion and migration. Yet, little is known about the function of F-BAR proteins in vivo. Here we report, that the F-BAR protein NOSTRIN is necessary for proper vascular development in zebrafish and postnatal retinal angiogenesis in mice. The loss of NOSTRIN impacts on the migration of endothelial tip cells and leads to a reduction of tip cell filopodia number and length. NOSTRIN forms a complex with the GTPase Rac1 and its exchange factor Sos1 and overexpression of NOSTRIN in cells induces Rac1 activation. Furthermore, NOSTRIN is required for fibroblast growth factor 2 dependent activation of Rac1 in primary endothelial cells and the angiogenic response to fibroblast growth factor 2 in the in vivo matrigel plug assay. We propose a novel regulatory circuit, in which NOSTRIN assembles a signalling complex containing FGFR1, Rac1 and Sos1 thereby facilitating the activation of Rac1 in endothelial cells during developmental angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Animals, Genetically Modified
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Animals, Newborn
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Blood Vessels / embryology*
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Blood Vessels / growth & development
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Blood Vessels / physiology
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CHO Cells
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Cells, Cultured
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Cricetinae
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Cricetulus
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Embryo, Mammalian
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Embryo, Nonmammalian
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Fibroblast Growth Factors / metabolism*
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Fibroblast Growth Factors / physiology
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Mice
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Mice, Knockout
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Models, Biological
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Neovascularization, Physiologic / genetics*
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism
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Receptor, Fibroblast Growth Factor, Type 1 / physiology
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Signal Transduction / genetics
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Signal Transduction / physiology
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Zebrafish / embryology
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Zebrafish / genetics
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Nostrin protein, mouse
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Fibroblast Growth Factors
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Fgfr1 protein, mouse
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Receptor, Fibroblast Growth Factor, Type 1