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

J. Biol. Chem., 13 September 2002
Vol. 277, Issue 37, p. 33690-33697
DOI: 10.1074/jbc.M202939200

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

  1. Mehdi Khaled,
  2. Lionel Larribere,
  3. Karine Bille,
  4. Edith Aberdam,
  5. Jean-Paul Ortonne,
  6. Robert Ballotti and
  7. Corine Bertolotto
  1. From INSERM U385, Biologie et Physiopathologie de la peau, IFR 50, 28, avenue de Valombrose, 06107 NICE Cedex 2, France

Abstract

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 3β (GSK3β), cAMP decreased the phosphorylation of GSK3β and stimulated its activity. Further, experiments were performed to investigate the role of GSK3β in the regulation of MITF expression and function. We observed that GSK3β regulated neither MITF promoter activity nor the intrinsic transcriptional activity of MITF but synergized with MITF to activate the tyrosinase promoter. Additionally, lithium, a GSK3β 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 GSK3β phosphorylates MITF and increases the ability of MITF to bind its target sequence, our results indicate that activation of GSK3β by cAMP facilitates MITF binding to the tyrosinase promoter, thereby leading to stimulation of melanogenesis.

  • Abbreviations:
    ACTH
    adrenocorticotrophic hormone
    GSK3β
    glycogen synthase kinase 3β
    GS peptide-2
    glycogen synthase peptide-2
    MITF
    microphthalmia-associated transcription factor
    αMSH
    α-melanocyte stimulating hormone
    PKA
    protein kinase A
    PI3K
    phosphatidylinositol 3-kinase
    ERK
    extracellular signal-regulated kinase
    MAPK
    mitogen-activated protein kinase
    CREB
    cAMP-response element-binding protein
    LT
    lethal toxin
    AEBSF
    4-(2-aminoethyl)-benzene-sulfonyl fluoride
    HA
    hemagglutinin
    • Received March 27, 2002.
    • Revision received June 20, 2002.

    Citation:

    M. Khaled, L. Larribere, K. Bille, E. Aberdam, J.-P. Ortonne, R. Ballotti, and C. Bertolotto, Glycogen Synthase Kinase 3β Is Activated by cAMP and Plays an Active Role in the Regulation of Melanogenesis. J. Biol. Chem. 277, 33690-33697 (2002).

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