Abstract
Endoglin (CD105) is an endothelial-specific transforming growth factor β (TGF-β) coreceptor essential for angiogenesis and vascular homeostasis. Although endoglin dysfunction contributes to numerous vascular conditions, the mechanism of endoglin action remains poorly understood. Here we report a novel mechanism in which endoglin and Gα-interacting protein C-terminus-interacting protein (GIPC)-mediated trafficking of phosphatidylinositol 3-kinase (PI3K) regulates endothelial signaling and function. We demonstrate that endoglin interacts with the PI3K subunits p110α and p85 via GIPC to recruit and activate PI3K and Akt at the cell membrane. Opposing ligand-induced effects are observed in which TGF-β1 attenuates, whereas bone morphogenetic protein-9 enhances, endoglin/GIPC-mediated membrane scaffolding of PI3K and Akt to alter endothelial capillary tube stability in vitro. Moreover, we employ the first transgenic zebrafish model for endoglin to demonstrate that GIPC is a critical component of endoglin function during developmental angiogenesis in vivo. These studies define a novel non-Smad function for endoglin and GIPC in regulating endothelial cell function during angiogenesis.
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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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, CD / metabolism*
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Antigens, CD / physiology
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Capillaries / cytology*
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Capillaries / growth & development
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Carrier Proteins / metabolism
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Cell Culture Techniques
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Cell Membrane / metabolism
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Cells, Cultured
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Endoglin
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Enzyme Activation
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Growth Differentiation Factor 2
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Growth Differentiation Factors / physiology
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Human Umbilical Vein Endothelial Cells / metabolism*
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Humans
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Mice
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Morphogenesis
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Neovascularization, Physiologic*
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Neuropeptides / metabolism
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Phosphatidylinositol 3-Kinases / metabolism*
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Protein Transport
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Proto-Oncogene Proteins c-akt / metabolism*
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Receptors, Cell Surface / metabolism*
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Receptors, Cell Surface / physiology
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Signal Transduction
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Transforming Growth Factor beta1 / 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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Antigens, CD
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Carrier Proteins
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ENG protein, human
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Endoglin
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GDF2 protein, human
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Gipc1 protein, mouse
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Growth Differentiation Factor 2
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Growth Differentiation Factors
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Neuropeptides
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Receptors, Cell Surface
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Transforming Growth Factor beta1
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Proto-Oncogene Proteins c-akt