Functional Roles for TGF-beta Superfamily Receptor-mediated Phosphorylation of the Cytoplasmic Domain of Endoglin on Endothelial Cell Signaling and Biology

dc.contributor.advisor

Blobe, Gerard C

dc.contributor.author

Ray, Bridgette

dc.date.accessioned

2009-01-02T16:24:54Z

dc.date.available

2011-07-26T04:30:03Z

dc.date.issued

2008-12-03

dc.department

Molecular Cancer Biology

dc.description.abstract

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.

dc.format.extent

4328191 bytes

dc.format.mimetype

application/pdf

dc.identifier.uri

https://hdl.handle.net/10161/915

dc.language.iso

en_US

dc.subject

Biology, Molecular

dc.title

Functional Roles for TGF-beta Superfamily Receptor-mediated Phosphorylation of the Cytoplasmic Domain of Endoglin on Endothelial Cell Signaling and Biology

dc.type

Dissertation

duke.embargo.months

24

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
D_Ray_Bridgette_a_200812.pdf
Size:
4.13 MB
Format:
Adobe Portable Document Format

Collections