Journal of Biological Chemistry
Volume 277, Issue 32, 9 August 2002, Pages 29197-29209
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MECHANISMS OF SIGNAL TRANSDUCTION
Extracellular and Cytoplasmic Domains of Endoglin Interact with the Transforming Growth Factor-β Receptors I and II*

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Endoglin is an auxiliary component of the transforming growth factor-β (TGF-β) receptor system, able to associate with the signaling receptor types I (TβRI) and II (TβRII) in the presence of ligand and to modulate the cellular responses to TGF-β1. Endoglin cannot bind ligand on its own but requires the presence of the signaling receptors, supporting a critical role for the interaction between endoglin and TβRI or TβRII. This study shows that full-length endoglin interacts with both TβRI and TβRII, independently of their kinase activation state or the presence of exogenous TGF-β1. Truncated constructs encoding either the extracellular or the cytoplasmic domains of endoglin demonstrated that the association with the signaling receptors occurs through both extracellular and cytoplasmic domains. However, a more specific mapping revealed that the endoglin/TβRI interaction was different from that of endoglin/TβRII. TβRII interacts with the amino acid region 437–558 of the extracellular domain of endoglin, whereas TβRI interacts not only with the region 437–558 but also with the protein region located between amino acid 437 and the N terminus. Both TβRI and TβRII interact with the cytoplasmic domain of endoglin, but TβRI only interacts when the kinase domain is inactive, whereas TβRII remains associated in its active and inactive forms. Upon association, TβRI and TβRII phosphorylate the endoglin cytoplasmic domain, and then TβRI, but not TβRII, kinase dissociates from the complex. Conversely, endoglin expression results in an altered phosphorylation state of TβRII, TβRI, and downstream Smad proteins as well as a modulation of TGF-β signaling, as measured by the reporter gene expression. These results suggest that by interacting through its extracellular and cytoplasmic domains with the signaling receptors, endoglin might affect TGF-β responses.

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Published, JBC Papers in Press, May 15, 2002, DOI 10.1074/jbc.M111991200

*

This work was supported by grants from Ministerio de Ciencia y Tecnologı́a (SAF2000-0132) and Comunidad Autónoma de Madrid (CAM).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a predoctoral fellowship from Ministerio de Ciencia y Tecnologı́a.

§

Supported by a predoctoral fellowship from CAM.

Present address: Dept. of Anatomy and Cell Biology, University of Toronto, Faculty of Medicine, Toronto, Ontario M5S 1A8, Canada.