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J. Biol. Chem., Vol. 282, Issue 29, 21507-21517, July 20, 2007

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The Interaction of Endoglin with -Arrestin2 Regulates Transforming Growth Factor--mediated ERK Activation and Migration in Endothelial Cells^*

From the Departments of Medicine, Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

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

Received for publication, January 8, 2007 , and in revised form, May 31, 2007.

^* This work was supported by National Institute of Health NCI Grant R01-CA105255 (to G. C. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 221B MSRB Research Dr., Box 2631 DUMC, Durham, NC 27710. Tel.: 919-668-1352; Fax: 919-668-2458; E-mail: blobe001{at}mc.duke.edu.

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