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J. Biol. Chem., Vol. 283, Issue 48, 33059-33068, November 28, 2008

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An Activin/Furin Regulatory Loop Modulates the Processing and Secretion of Inhibin - and β_B-Subunit Dimers in Pituitary Gonadotrope Cells^*

Monica Antenos, Jie Zhu, Niti M. Jetly, and Teresa K. Woodruff^¶1

From the Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, the Center for Reproductive Science, Northwestern University, Evanston, Illinois 60208, and the ^¶Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611

Of all ligands of the transforming growth factor β superfamily, inhibins and activins are a physiologically relevant pair that are functional antagonists of each other. Activin stimulates whereas inhibin blocks follicle-stimulating hormone biosynthesis and secretion from pituitary gonadotrope cells, and together, inhibin and activin control the pituitary gonadal axis essential for normal reproductive function. Sharing a similar β-subunit, the secretion of inhibin heterodimers (/β) or activin homodimers (β/β) as mature bioactive ligands depends, in part, on the proteolytic processing of precursor proteins. A short loop regulatory pathway controlling precursor processing and dimer secretion was discovered. Activin stimulates endogenous inhibin - and β_B-subunit mRNA, protein, and proteolytic processing. Simultaneously, activin stimulated the proconvertase furin through a Smad2/3-dependent process. The data provide a mechanism where the regulation of furin and inhibin subunits cooperates in an important positive short feedback loop. This regulatory loop augments the secretion of bioactive mature activin B, as well as inhibin B dimers, necessary for local follicle-stimulating hormone β regulation.

Received for publication, May 30, 2008 , and in revised form, September 24, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01 HD37096. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Obstetrics and Gynecology, Northwestern University, Feinburg School of Medicine, Lurie 10-250 303 E Superior St., Chicago, IL 60611. Tel.: 312-503-2535; Fax: 312-503-5607; E-mail: tkw{at}northwestern.edu.

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