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J. Biol. Chem. 277 (37): 33690-33697

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Glycogen Synthase Kinase 3beta Is Activated by cAMP and Plays an Active Role in the Regulation of Melanogenesis*

Mehdi Khaled, Lionel Larribere, Karine Bille, Edith Aberdam, Jean-Paul Ortonne, Robert Ballotti, and Corine BertolottoDagger

From INSERM U385, Biologie et Physiopathologie de la peau, IFR 50, 28, avenue de Valombrose, 06107 NICE Cedex 2, France

In human and mouse, cAMP plays a key role in the control of pigmentation. cAMP, through the activation of protein kinase A, increases the expression of microphthalmia-associated transcription factor (MITF), which in turn stimulates tyrosinase gene expression, to allow melanin synthesis. Beyond this simplified scheme, cAMP inhibits phosphatidylinositol 3-kinase (PI3K), and inhibition of PI3K, by a specific inhibitor, stimulates melanogenesis. However, the link between the PI3K pathway and melanogenesis remained to be elucidated. In this report, we showed that cAMP, through a protein kinase A-independent mechanism, led to inhibition of AKT phosphorylation and activity. Consistent with the role of AKT in the regulation of glycogen synthase kinase 3beta (GSK3beta ), cAMP decreased the phosphorylation of GSK3beta and stimulated its activity. Further, experiments were performed to investigate the role of GSK3beta in the regulation of MITF expression and function. We observed that GSK3beta regulated neither MITF promoter activity nor the intrinsic transcriptional activity of MITF but synergized with MITF to activate the tyrosinase promoter. Additionally, lithium, a GSK3beta inhibitor, impaired the response of the tyrosinase promoter to cAMP, and cAMP increased the binding of MITF to the M-box. Taking into account that GSK3beta phosphorylates MITF and increases the ability of MITF to bind its target sequence, our results indicate that activation of GSK3beta by cAMP facilitates MITF binding to the tyrosinase promoter, thereby leading to stimulation of melanogenesis.

* This work was supported by grants from INSERM and The Ligue Nationale contre le Cancer and by Grant 5808 from the Association pour la Recherche sur le Cancer.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.

Dagger To whom correspondence should be addressed. Tel.: 33-4-93-37-77-90; Fax: 33-4-93-81-14-04; E-mail: bertolot@unice.fr.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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