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J. Biol. Chem., Vol. 278, Issue 24, 22128-22135, June 13, 2003
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Transcription Factor GATA-4 Is Activated by Phosphorylation of Serine 261 via the cAMP/Protein Kinase A Signaling Pathway in Gonadal Cells*
From the Ontogeny and Reproduction Research Unit, Centre Hospitalier de l'Université Laval Research Centre and Centre de Recherche en Biologie de la Reproduction, Department of Obstetrics and Gynecology, Université Laval, Ste-Foy, Québec G1V 4G2, Canada
Gonadal gene expression is regulated by pituitary hormones acting through the cAMP/protein kinase A (PKA) signal transduction pathway. The downstream molecular effectors of these signals, however, have yet to be fully understood. We have recently shown that cAMP stimulation of gonadal cells leads to phosphorylation of the transcription factor GATA-4, a key regulator of gonadal gene expression, thus suggesting that this factor might be a novel target for the cAMP/PKA signaling pathway. We now show that the rapid phosphorylation of GATA-4 induced by cAMP in vivo can be blocked by a PKA-specific inhibitor but not by mitogen-activated protein kinase inhibitors, indicating that GATA-4 is predominantly phosphorylated by PKA in response to cAMP in gonadal cells. In addition, using in vitro kinase assays, we show that PKA phosphorylation of GATA-4 occurs predominantly on an evolutionarily conserved serine residue located at position 261. Phosphorylation of GATA-4 Ser261 by PKA enhances its transcriptional activity on different gonadal promoters, an effect that was markedly reduced with a S261A mutant. Moreover, the S261A mutant blunted cAMP-induced promoter activity in gonadal cells. Finally, PKA-dependent phosphorylation of GATA-4 also led to enhanced recruitment of the CREB-binding protein coactivator. This recruitment and transcriptional cooperation were dramatically impaired with the S261A mutant. Thus, our results identify GATA-4 as a novel downstream effector of cAMP/PKA signaling in gonadal cells, where phosphorylation of Ser261 and recruitment of CREB-binding protein likely represent a key mechanism for conveying the cAMP responsiveness of gonadal genes that lack classical cAMP regulatory elements.
Received for publication, December 23, 2002 , and in revised form, March 10, 2003.
* This work was supported by grants from the Canadian Institutes of Health Research and the Cancer Research Society Inc. (to R. S. V.). 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.
Recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research.
Canada Research Chair in Reproduction and Sex Development. To whom correspondence should be addressed: Ontogeny and Reproduction, Rm. T1–49, CHUL Research Centre, 2705 Laurier Blvd., Ste-Foy, PQ G1V 4G2, Canada. E-mail: Robert.Viger{at}crchul.ulaval.ca.
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