Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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:

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

Pseudomonas aeruginosa Exotoxin Y Is a Promiscuous Cyclase That Increases Endothelial Tau Phosphorylation and Permeability.
C. D. Ochoa, M. Alexeyev, V. Pastukh, R. Balczon, and T. Stevens (2012)
J. Biol. Chem. 287, 25407-25418
   Abstract »    Full Text »    PDF »
The E-box Binding Factors Max/Mnt, MITF, and USF1 Act Coordinately with FoxO to Regulate Expression of Proapoptotic and Cell Cycle Control Genes by Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3 Signaling.
J. Terragni, G. Nayak, S. Banerjee, J.-L. Medrano, J. R. Graham, J. F. Brennan, S. Sepulveda, and G. M. Cooper (2011)
J. Biol. Chem. 286, 36215-36227
   Abstract »    Full Text »    PDF »
Sesamin induces melanogenesis by microphthalmia-associated transcription factor and tyrosinase up-regulation via cAMP signaling pathway.
Z. Jiang, S. Li, Y. Liu, P. Deng, J. Huang, and G. He (2011)
Acta Biochim Biophys Sin 43, 763-770
   Abstract »    Full Text »    PDF »
MicroRNA-340-mediated Degradation of Microphthalmia-associated Transcription Factor mRNA Is Inhibited by the Coding Region Determinant-binding Protein.
S. Goswami, R. S. Tarapore, J. J. TeSlaa, Y. Grinblat, V. Setaluri, and V. S. Spiegelman (2010)
J. Biol. Chem. 285, 20532-20540
   Abstract »    Full Text »    PDF »
Phosphorylation of beta-Catenin by Cyclic AMP-dependent Protein Kinase.
S. Taurin, N. Sandbo, Y. Qin, D. Browning, and N. O. Dulin (2006)
J. Biol. Chem. 281, 9971-9976
   Abstract »    Full Text »    PDF »
The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis.
L. Larribere, C. Hilmi, M. Khaled, C. Gaggioli, K. Bille, P. Auberger, J. P. Ortonne, R. Ballotti, and C. Bertolotto (2005)
Genes & Dev. 19, 1980-1985
   Abstract »    Full Text »    PDF »
Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells.
R. Busca, E. Berra, C. Gaggioli, M. Khaled, K. Bille, B. Marchetti, R. Thyss, G. Fitsialos, L. Larribere, C. Bertolotto, et al. (2005)
J. Cell Biol. 170, 49-59
   Abstract »    Full Text »    PDF »
Involvement of Phospholipase D1 in Melanogenesis of Mouse B16 Melanoma Cells.
K. Ohguchi, Y. Banno, Y. Akao, and Y. Nozawa (2004)
J. Biol. Chem. 279, 3408-3412
   Abstract »    Full Text »    PDF »
Sphingosine-1-phosphate decreases melanin synthesis via sustained ERK activation and subsequent MITF degradation.
D.-S. Kim, E.-S. Hwang, J.-E. Lee, S.-Y. Kim, S.-B. Kwon, and K.-C. Park (2003)
J. Cell Sci. 116, 1699-1706
   Abstract »    Full Text »    PDF »
GSK-3: tricks of the trade for a multi-tasking kinase.
B. W. Doble and J. R. Woodgett (2003)
J. Cell Sci. 116, 1175-1186
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882