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J. Biol. Chem., Vol. 280, Issue 30, 27800-27808, July 29, 2005

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Endoglin Null Endothelial Cells Proliferate Faster and Are More Responsive to Transforming Growth Factor 1 with Higher Affinity Receptors and an Activated Alk1 Pathway^*

Nadia Pece-Barbara, Sonia Vera¶, Kirishanthy Kathirkamathamby¶||, Stefan Liebner**, Gianni M. Di Guglielmo, Elisabetta Dejana**, Jeffrey L. Wrana, and Michelle Letarte¶||

From the Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, the ^¶Cancer Research Program, Hospital for Sick Children, and the ^||Heart and Stroke Lewar Center of Excellence and Department of Immunology, University of Toronto, Ontario M5G 1X8, Canada and ^**Italian Foundation for Cancer Research Institute of Molecular Oncology and Department of Biomolecular and Biotechnological Sciences, University of Milan, Milan 20146, Italy

Endoglin is an accessory receptor for transforming growth factor (TGF) in endothelial cells, essential for vascular development. Its pivotal role in angiogenesis is underscored in Endoglin null (Eng^-/-) murine embryos, which die at mid-gestation (E10.5) from impaired yolk sac vessel formation. Moreover, mutations in endoglin and the endothelial-specific TGF type I receptor, ALK1, are linked to hereditary hemorrhagic telangiectasia. To determine the role of endoglin in TGF pathways, we derived murine endothelial cell lines from Eng^+/+ and Eng^-/- embryos (E9.0). Whereas Eng^+/+ cells were only partially growth inhibited by TGF, Eng^-/- cells displayed a potent anti-proliferative response. TGF-dependent Smad2 phosphorylation and Smad2/3 translocation were unchanged in the Eng^-/- cells. In contrast, TGF treatment led to a more rapid activation of the Smad1/5 pathway in Eng null cells that was apparent at lower TGF concentrations. Enhanced activity of the Smad1 pathway in Eng^-/- cells was reflected in higher expression of ALK1-dependent genes such as Id1, Smad6, and Smad7. Analysis of cell surface receptors revealed that the TGF type I receptor, ALK5, which is required for ALK1 function, was increased in Eng^-/- cells. TGF receptor complexes were less numerous but displayed a higher binding affinity. These results suggest that endoglin modulates TGF signaling in endothelial cells by regulating surface TGF receptors and suppressing Smad1 activation. Thus an altered balance in TGF receptors and downstream Smad pathways may underlie defects in vascular development and homeostasis.

Received for publication, March 30, 2005 , and in revised form, May 23, 2005.

^* This work was supported in part by grants from the Canadian Institute of Health Research (to J. L. W. and M. L.), the Heart and Stroke Foundation of Canada (to M. L.), and the National Cancer Institute of Canada (to J. L. W.). 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.

Recipient of a postdoctoral fellowship from the Canadian Digestive Disease Foundation/Canadian Institutes of Health Research.

An International Scholar of the Howard Hughes Medical Institute.

To whom correspondence should be addressed: Cancer Research Program, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-6258; Fax: 416-813-6255; E-mail: mablab{at}sickkids.ca.

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