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Originally published In Press as doi:10.1074/jbc.M209710200 on December 18, 2002

J. Biol. Chem., Vol. 278, Issue 10, 7934-7941, March 7, 2003
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Inhibin Is an Antagonist of Bone Morphogenetic Protein Signaling*

Ezra WiaterDagger and Wylie Vale§

From the Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037 and Dagger  Department of Biology Graduate Program, University of California, San Diego, La Jolla, California 92093

Inhibins are endogenous antagonists of activin signaling, long recognized as important regulators of gonadal function and pituitary FSH release. Inhibin, in concert with its co-receptor, betaglycan, can compete with activin for binding to type II activin receptors and, thus, prevent activin signaling. Because bone morphogenetic proteins (BMPs) also utilize type II activin receptors, we hypothesized that BMP signaling might also be sensitive to inhibin blockade. Here we show that inhibin blocks cellular responses to diverse BMP family members in a variety of BMP-responsive cell types. Inhibin abrogates BMP-induced Smad signaling and transcription responses. Inhibin competes with BMPs for type II activin receptors, and this competition is facilitated by betaglycan. Betaglycan also enables inhibin to bind to and compete with BMPs for binding to the BMP-specific type II receptor BMPRII, which does not bind inhibin in the absence of betaglycan. Betaglycan can confer inhibin responsiveness on cells that are otherwise insensitive to inhibin. These findings demonstrate that inhibin, acting through betaglycan, can function as an antagonist of BMP responses, suggesting a broader role for inhibin and betaglycan in restricting and refining a wide spectrum of transforming growth factor beta  superfamily signals.

* This work was supported by National Institutes of Health Program Project Grant HD13527 and by The Kleberg Foundation and the Foundation for Medical Research, Inc.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.

§ An FMR, Inc., Senior Investigator. To whom correspondence should be addressed. Fax: 858-552-1546; E-mail: vale@salk.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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