Endoglin mediates fibronectin/?5?1 integrin and TGF-? pathway crosstalk in endothelial cells.

ABSTRACT: Both the transforming growth factor ? (TGF-?) 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, ?5?1 integrin, specifically increase TGF-?1- and BMP-9-induced Smad1/5/8 phosphorylation via the TGF-? superfamily receptors endoglin and activin-like kinase-1 (ALK1). Fibronectin and ?5?1 integrin increase Smad1/5/8 signalling by promoting endoglin/ALK1 cell surface complex formation. In a reciprocal manner, TGF-?1 activates ?5?1 integrin and downstream signalling to focal adhesion kinase (FAK) in an endoglin-dependent manner. ?5?1 integrin and endoglin form a complex on the cell surface and co-internalize, with their internalization regulating ?5?1 integrin activation and signalling. Functionally, endoglin-mediated fibronectin/?5?1 integrin and TGF-? pathway crosstalk alter the responses of endothelial cells to TGF-?1, switching TGF-?1 from a promoter to a suppressor of migration, inhibiting TGF-?1-mediated apoptosis to promote capillary stability, and partially mediating developmental angiogenesis in vivo. These studies provide a novel mechanism for the regulation of TGF-? superfamily signalling and endothelial function through crosstalk with integrin signalling pathways.

SUBMITTER: Tian H 

PROVIDER: S-EPMC3463850 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other