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<p>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.</p>
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