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Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC.

Publication ,  Journal Article
Lee, NY; Ray, B; How, T; Blobe, GC
Published in: J Biol Chem
November 21, 2008

Transforming growth factor beta (TGF-beta) signals through two distinct pathways to regulate endothelial cell proliferation, migration, and angiogenesis, the ALK-1/Smad 1/5/8 and ALK-5/Smad2/3 pathways. Endoglin is a co-receptor predominantly expressed in endothelial cells that participates in TGFbeta-mediated signaling with ALK-1 and ALK-5 and regulates critical aspects of cellular and biological responses. The embryonic lethal phenotype of knock-out mice because of defects in angiogenesis and disease-causing mutations resulting in human vascular diseases both support essential roles for endoglin, ALK-1, and ALK-5 in the vasculature. However, the mechanism by which endoglin mediates TGF-beta signaling through ALK-1 and ALK-5 has remained elusive. Here we describe a novel interaction between endoglin and GIPC, a scaffolding protein known to regulate cell surface receptor expression and trafficking. Co-immunoprecipitation and immunofluorescence confocal studies both demonstrate a specific interaction between endoglin and GIPC in endothelial cells, mediated by a class I PDZ binding motif in the cytoplasmic domain of endoglin. Subcellular distribution studies demonstrate that endoglin recruits GIPC to the plasma membrane and co-localizes with GIPC in a TGFbeta-independent manner, with GIPC-promoting cell surface retention of endoglin. Endoglin specifically enhanced TGF-beta1-induced phosphorylation of Smad 1/5/8, increased a Smad 1/5/8 responsive promoter, and inhibited endothelial cell migration in a manner dependent on the ability of endoglin to interact with GIPC. These studies define a novel mechanism for the regulation of endoglin signaling and function in endothelial cells and demonstrate a new role for GIPC in TGF-beta signaling.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 21, 2008

Volume

283

Issue

47

Start / End Page

32527 / 32533

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Smad8 Protein
  • Smad5 Protein
  • Smad1 Protein
  • Signal Transduction
  • Sequence Homology, Amino Acid
  • Receptors, Cell Surface
  • Neuropeptides
  • Molecular Sequence Data
  • Mice, Transgenic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lee, N. Y., Ray, B., How, T., & Blobe, G. C. (2008). Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. J Biol Chem, 283(47), 32527–32533. https://doi.org/10.1074/jbc.M803059200
Lee, Nam Y., Bridgette Ray, Tam How, and Gerard C. Blobe. “Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC.J Biol Chem 283, no. 47 (November 21, 2008): 32527–33. https://doi.org/10.1074/jbc.M803059200.
Lee, Nam Y., et al. “Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC.J Biol Chem, vol. 283, no. 47, Nov. 2008, pp. 32527–33. Pubmed, doi:10.1074/jbc.M803059200.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 21, 2008

Volume

283

Issue

47

Start / End Page

32527 / 32533

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Smad8 Protein
  • Smad5 Protein
  • Smad1 Protein
  • Signal Transduction
  • Sequence Homology, Amino Acid
  • Receptors, Cell Surface
  • Neuropeptides
  • Molecular Sequence Data
  • Mice, Transgenic