Functional Roles for TGF-beta Superfamily Receptor-mediated Phosphorylation of the Cytoplasmic Domain of Endoglin on Endothelial Cell Signaling and Biology
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Endoglin, an endothelial cell specific transforming growth factor-beta (TGF-beta) superfamily co-receptor, has an essential role in angiogenesis, with endoglin null mice having an embryonic lethal phenotype due to defects in angiogenesis and mutations in endoglin resulting in the vascular disease hereditary hemorrhagic telangiectasia type I. While endoglin is thought to regulate TGF-beta superfamily signaling in endothelial cells through regulating the balance between two TGF-beta responsive pathways, the ALK5/Smad2/3 pathway and the ALK1/Smad1/5/8 pathway, the mechanism by which endoglin regulates angiogenesis has not been defined. Recently, overexpression of wild type endoglin has been demonstrated to increase ALK1 signaling, supporting a role for endoglin as an important regulator of the ALK1 pathway. Here we investigate the role of the cytoplasmic domain of endoglin and its phosphorylation by TGF-beta superfamily receptors in regulating endoglin function in endothelial cells. We demonstrate that the cytoplasmic domain of endoglin is basally phosphorylated by ALK5, primarily on serines 646 and 649, in endothelial cells. This basal phosphorylation primes and is necessary for subsequent phosphorylation of endoglin by ALK1. Functionally, the loss of phosphorylation at serine 646 resulted in a loss of endoglin mediated inhibition of Smad1/5/8 signaling and endothelial cell migration. Taken together these results support endoglin phosphorylation by ALK5 as an important mechanism for regulating TGF-beta superfamily signaling and migration in endothelial cells.
Ray, Bridgette (2008). Functional Roles for TGF-beta Superfamily Receptor-mediated Phosphorylation of the Cytoplasmic Domain of Endoglin on Endothelial Cell Signaling and Biology. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/915.
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