Endoglin mediates fibronectin/a5b1 integrin and TGF-b pathway crosstalk in endothelial cells

Both the transforming growth factor b (TGF-b) 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, a5b1 integrin, specifically increase TGF-b1and BMP-9-induced Smad1/5/8 phosphorylation via the TGF-b superfamily receptors endoglin and activin-like kinase-1 (ALK1). Fibronectin and a5b1 integrin increase Smad1/5/8 signalling by promoting endoglin/ ALK1 cell surface complex formation. In a reciprocal manner, TGF-b1 activates a5b1 integrin and downstream signalling to focal adhesion kinase (FAK) in an endoglindependent manner. a5b1 integrin and endoglin form a complex on the cell surface and co-internalize, with their internalization regulating a5b1 integrin activation and signalling. Functionally, endoglin-mediated fibronectin/ a5b1 integrin and TGF-b pathway crosstalk alter the responses of endothelial cells to TGF-b1, switching TGF-b1 from a promoter to a suppressor of migration, inhibiting TGF-b1-mediated apoptosis to promote capillary stability, and partially mediating developmental angiogenesis in vivo. These studies provide a novel mechanism for the regulation of TGF-b superfamily signalling and endothelial function through crosstalk with integrin signalling pathways. The EMBO Journal (2012) 31, 3885–3900. doi:10.1038/ emboj.2012.246; Published online 31 August 2012 Subject Categories: cell & tissue architecture; signal transduction