title: Endoglin mediates fibronectin/α5β1 integrin and TGF-β pathway crosstalk in endothelial cells.
abstract: Both the transforming growth factor β (TGF-β) and integrin signalling pathways have well-established roles in angiogenesis. However, how these pathways integrate to regulate angiogenesis is unknown. Here, we show that the extracellular matrix component, fibronectin, and its cellular receptor, α5β1 integrin, specifically increase TGF-β1- and BMP-9-induced Smad1/5/8 phosphorylation via the TGF-β superfamily receptors endoglin and activin-like kinase-1 (ALK1). Fibronectin and α5β1 integrin increase Smad1/5/8 signalling by promoting endoglin/ALK1 cell surface complex formation. In a reciprocal manner, TGF-β1 activates α5β1 integrin and downstream signalling to focal adhesion kinase (FAK) in an endoglin-dependent manner. α5β1 integrin and endoglin form a complex on the cell surface and co-internalize, with their internalization regulating α5β1 integrin activation and signalling. Functionally, endoglin-mediated fibronectin/α5β1 integrin and TGF-β pathway crosstalk alter the responses of endothelial cells to TGF-β1, switching TGF-β1 from a promoter to a suppressor of migration, inhibiting TGF-β1-mediated apoptosis to promote capillary stability, and partially mediating developmental angiogenesis in vivo. These studies provide a novel mechanism for the regulation of TGF-β superfamily signalling and endothelial function through crosstalk with integrin signalling pathways.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Tian
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Mythreye
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D055806:Microvessels / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D005353:Fibronectins; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D039081:Integrin alpha5beta1; D011956:Receptors, Cell Surface; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; C107514:SMAD9 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D053773:Transforming Growth Factor beta1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II