Endoglin Regulates PI3-Kinase/Akt Trafficking and Signaling to Alter Endothelial Capillary Stability During Angiogenesis
- Authors
- Lee, N.Y., Golzio, C., Gatza, C.E., Sharma, A., Katsanis, N., and Blobe, G.C.
- ID
- ZDB-PUB-120522-4
- Date
- 2012
- Source
- Molecular biology of the cell 23(13): 2412-2423 (Journal)
- Registered Authors
- Katsanis, Nicholas
- Keywords
- none
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing
- Animals
- Antigens, CD/metabolism*
- Antigens, CD/physiology
- Capillaries/cytology*
- Capillaries/growth & development
- Carrier Proteins/metabolism
- Cell Culture Techniques
- Cell Membrane/metabolism
- Cells, Cultured
- Enzyme Activation
- Growth Differentiation Factors/physiology
- Human Umbilical Vein Endothelial Cells/metabolism*
- Humans
- Mice
- Morphogenesis
- Neovascularization, Physiologic*
- Neuropeptides/metabolism
- Phosphatidylinositol 3-Kinases/metabolism*
- Protein Transport
- Proto-Oncogene Proteins c-akt/metabolism*
- Receptors, Cell Surface/metabolism*
- Receptors, Cell Surface/physiology
- Signal Transduction
- Transforming Growth Factor beta1/physiology
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 22593212 Full text @ Mol. Biol. Cell
Endoglin (CD105) is an endothelial-specific TGF-β coreceptor essential for angiogenesis and vascular homeostasis. While 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 GIPC-mediated trafficking of PI3-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 BMP-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 the endothelial cell function during angiogenesis.