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J. Biol. Chem., Vol. 278, Issue 23, 21197-21203, June 6, 2003

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Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary^*

Bernhard Schmierer, Michael K. Schuster, Alena Shkumatava and Karl Kuchler 

From the Institute of Medical Biochemistry, Department of Molecular Genetics, University and BioCenter of Vienna, A-1030 Vienna, Austria

Activin A signaling is an important regulator of ovarian granulosa cell function. The cytosolic signal transducer Smad2 is most highly expressed in chicken granulosa cells (cGC) of preovulatory follicles. Moreover, Smad2 shows predominant nuclear localization in freshly isolated cGC, indicating active Smad signaling in vivo. Primary cGC cultured in vitro require activin A to sustain high Smad2 levels, which otherwise drop dramatically in the absence of activin A. This activin A-dependent Smad2 expression is abrogated by protein kinase A (PKA) inhibitors, suggesting a role for PKA in activin signaling. In the absence of activin A, strong PKA activators such as follicle-stimulating hormone (FSH) and 8-bromo-cyclic AMP fail to elicit Smad2 induction. However, FSH and 8-bromo-cyclic AMP boost activin A-dependent Smad2 up-regulation, giving rise to Smad2 levels similar to expression in vivo levels. Interestingly, the effect is specific for Smad2, since expression of the structurally and functionally closely related Smad3 remains entirely unaffected. Hence, activin A induces Smad2, but not Smad3, to high levels requiring PKA activation. Since Smad2 and Smad3 target distinct yet overlapping sets of TGF-/activin-responsive genes, the selective Smad2 induction by FSH/activin A could allow FSH to efficiently modulate the transcriptional readout of activin A signaling in avian granulosa cells.

Received for publication, December 6, 2002 , and in revised form, March 12, 2003.

^* This work was supported by funds from Austrian Science Foundation Grant SFB-604 (to K. K.). 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.

To whom correspondence and reprint requests should be addressed: Institute of Medical Biochemistry, Department for Molecular Genetics, University and BioCenter of Vienna, Dr. Bohr-Gasse 9/2, A-1030, Vienna, Austria. Tel.: 43-1-4277-61807; Fax: 43-1-4277-9618; E-mail: kaku{at}mol.univie.ac.at.

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