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The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-beta-mediated ERK activation and migration in endothelial cells.

Publication ,  Journal Article
Lee, NY; Blobe, GC
Published in: J Biol Chem
July 20, 2007

In endothelial cells, transforming growth factor beta (TGF-beta) signals through two distinct pathways to regulate endothelial cell proliferation and migration, the ALK-1/Smads 1/5/8 pathway and the ALK-5/Smads 2/3 pathway. TGF-beta signaling through these pathways is further regulated in endothelial cells by the endothelial specific TGF-beta superfamily co-receptor, endoglin. The importance of endoglin, ALK-1, and ALK-5 in endothelial biology is underscored by the embryonic lethal phenotypes of knock-outs in mice due to defects in angiogenesis, and by the presence of disease-causing mutations in these genes in human vascular diseases. However, the mechanism of action of endoglin is not well defined. Here we define a novel interaction between endoglin and the scaffolding protein beta-arrestin2. Both co-immunoprecipitation and fluorescence confocal studies demonstrate the specific interaction between endoglin and beta-arrestin2 in endothelial cells, enhanced by ALK-1 and to a lesser extent by the type II TGF-beta receptor. The endoglin/beta-arrestin2 interaction results in endoglin internalization and co-accumulation of endoglin and beta-arrestin2 in endocytic vesicles. Whereas endoglin did not have a direct impact on either Smad 2/3 or Smad 1/5/8 activation, endoglin antagonized TGF-beta-mediated ERK signaling, altered the subcellular distribution of activated ERK, and inhibited endothelial cell migration in a manner dependent on the ability of endoglin to interact with beta-arrestin2. Reciprocally, small interfering RNA-mediated silencing of endogenous beta-arrestin2 expression restored TGF-beta-mediated ERK activation and increased endothelial cell migration in an endoglin-dependent manner. These studies define a novel function for endoglin, and further expand the roles mediated by the ubiquitous scaffolding protein beta-arrestin2.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 20, 2007

Volume

282

Issue

29

Start / End Page

21507 / 21517

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Wound Healing
  • Transforming Growth Factor beta
  • Signal Transduction
  • Receptors, Cell Surface
  • Protein Binding
  • Mice
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • Extracellular Signal-Regulated MAP Kinases
 

Citation

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Lee, N. Y., & Blobe, G. C. (2007). The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-beta-mediated ERK activation and migration in endothelial cells. J Biol Chem, 282(29), 21507–21517. https://doi.org/10.1074/jbc.M700176200
Lee, Nam Y., and Gerard C. Blobe. “The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-beta-mediated ERK activation and migration in endothelial cells.J Biol Chem 282, no. 29 (July 20, 2007): 21507–17. https://doi.org/10.1074/jbc.M700176200.
Lee, Nam Y., and Gerard C. Blobe. “The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-beta-mediated ERK activation and migration in endothelial cells.J Biol Chem, vol. 282, no. 29, July 2007, pp. 21507–17. Pubmed, doi:10.1074/jbc.M700176200.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 20, 2007

Volume

282

Issue

29

Start / End Page

21507 / 21517

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Wound Healing
  • Transforming Growth Factor beta
  • Signal Transduction
  • Receptors, Cell Surface
  • Protein Binding
  • Mice
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • Extracellular Signal-Regulated MAP Kinases