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ALK5 phosphorylation of the endoglin cytoplasmic domain regulates Smad1/5/8 signaling and endothelial cell migration.

Publication ,  Journal Article
Ray, BN; Lee, NY; How, T; Blobe, GC
Published in: Carcinogenesis
March 2010

Endoglin, an endothelial cell-specific transforming growth factor-beta (TGF-beta) superfamily coreceptor, has an essential role in angiogenesis. Endoglin-null mice have an embryonic lethal phenotype due to defects in angiogenesis and mutations in endoglin result in the vascular disease hereditary hemorrhagic telangiectasia type I. Increased endoglin expression in the proliferating endothelium of tumors has been correlated with metastasis, tumor grade and decreased survival. Although endoglin is thought to regulate TGF-beta superfamily signaling in endothelial cells through regulating the balance between two TGF-beta-responsive pathways, the activin receptor-like kinase 5 (ALK5)/Smad2/3 pathway and the activin receptor-like kinase 1 (ALK1)/Smad1/5/8 pathway, the mechanism by which endoglin regulates angiogenesis has not been defined. Here, we investigate the role of the cytoplasmic domain of endoglin and its phosphorylation by ALK5 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. Functionally, the loss of phosphorylation at serine 646 resulted in a loss of endoglin-mediated inhibition of Smad1/5/8 signaling in response to TGF-beta and endothelial cell migration, whereas loss of phosphorylation at both serines 646 and 649 resulted in a loss of endoglin-mediated inhibition of Smad1/5/8 signaling in response to bone morphogenetic protein-9. Taken together, these results support endoglin phosphorylation by ALK5 as an important mechanism for regulating TGF-beta superfamily signaling and migration in endothelial cells.

Duke Scholars

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

March 2010

Volume

31

Issue

3

Start / End Page

435 / 441

Location

England

Related Subject Headings

  • Transforming Growth Factor beta
  • Smad8 Protein
  • Smad5 Protein
  • Smad1 Protein
  • Signal Transduction
  • Receptors, Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type I
  • Protein Structure, Tertiary
  • Protein Serine-Threonine Kinases
  • Protein Processing, Post-Translational
 

Citation

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ICMJE
MLA
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Ray, B. N., Lee, N. Y., How, T., & Blobe, G. C. (2010). ALK5 phosphorylation of the endoglin cytoplasmic domain regulates Smad1/5/8 signaling and endothelial cell migration. Carcinogenesis, 31(3), 435–441. https://doi.org/10.1093/carcin/bgp327
Ray, Bridgette N., Nam Y. Lee, Tam How, and Gerard C. Blobe. “ALK5 phosphorylation of the endoglin cytoplasmic domain regulates Smad1/5/8 signaling and endothelial cell migration.Carcinogenesis 31, no. 3 (March 2010): 435–41. https://doi.org/10.1093/carcin/bgp327.
Ray, Bridgette N., et al. “ALK5 phosphorylation of the endoglin cytoplasmic domain regulates Smad1/5/8 signaling and endothelial cell migration.Carcinogenesis, vol. 31, no. 3, Mar. 2010, pp. 435–41. Pubmed, doi:10.1093/carcin/bgp327.
Journal cover image

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

March 2010

Volume

31

Issue

3

Start / End Page

435 / 441

Location

England

Related Subject Headings

  • Transforming Growth Factor beta
  • Smad8 Protein
  • Smad5 Protein
  • Smad1 Protein
  • Signal Transduction
  • Receptors, Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type I
  • Protein Structure, Tertiary
  • Protein Serine-Threonine Kinases
  • Protein Processing, Post-Translational