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J. Biol. Chem., Vol. 277, Issue 32, 29197-29209, August 9, 2002
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From the Centro de Investigaciones Biológicas, Consejo
Superior de Investigaciones Científicas, Velázquez 144, Madrid 28006, Spain
Endoglin is an auxiliary component of the
transforming growth factor-
Extracellular and Cytoplasmic Domains of Endoglin Interact with
the Transforming Growth Factor-
Receptors I and II*
,
(TGF-) receptor system, able to
associate with the signaling receptor types I (TRI) and II (TRII)
in the presence of ligand and to modulate the cellular responses to
TGF-1. 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 TRI or TRII. This study shows
that full-length endoglin interacts with both TRI and TRII,
independently of their kinase activation state or the presence of
exogenous TGF-1. 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/TRI interaction was different from that
of endoglin/TRII. TRII interacts with the amino acid region
437-558 of the extracellular domain of endoglin, whereas TRI
interacts not only with the region 437-558 but also with the protein
region located between amino acid 437 and the N terminus. Both TRI
and TRII interact with the cytoplasmic domain of endoglin, but
TRI only interacts when the kinase domain is inactive, whereas
TRII remains associated in its active and inactive forms. Upon
association, TRI and TRII phosphorylate the endoglin cytoplasmic
domain, and then TRI, but not TRII, kinase dissociates from the
complex. Conversely, endoglin expression results in an altered
phosphorylation state of TRII, TRI, and downstream Smad proteins
as well as a modulation of TGF- 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- responses.
*
This work was supported by grants from Ministerio de Ciencia
y Tecnología (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
Tecnología.
§
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.
To whom correspondence should be addressed. Fax:
34-91-5627518; E-mail: bernabeu.c@cib.csic.es.
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