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

Nam Y. Lee, Gerard C. Blobe

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

In endothelial cells, transforming growth factor β (TGF-β) 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-β signaling through these pathways is further regulated in endothelial cells by the endothelial specific TGF-β 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 β-arrestin2. Both co- immunoprecipitation and fluorescence confocal studies demonstrate the specific interaction between endoglin and β-arrestin2 in endothelial cells, enhanced by ALK-1 and to a lesser extent by the type II TGF-β receptor. The endoglin/β-arrestin2 interaction results in endoglin internalization and co-accumulation of endoglin and β-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-β-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 β-arrestin2. Reciprocally, small interfering RNA-mediated silencing of endogenous β-arrestin2 expression restored TGF-β-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 β-arrestin2.

Original languageEnglish (US)
Pages (from-to)21507-21517
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number29
DOIs
StatePublished - Jul 20 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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