Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter

Maria Ekerot, Marios P. Stavridis, Laurent Delavaine, Michael P. Mitchell, Christopher Staples, David M. Owens, Iain D. Keenan, Robin J. Dickinson, Kate G. Storey, Stephen M. Keyse (Lead / Corresponding author)

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    Abstract

    DUSP6 (dual-specificity phosphatase 6), also known as MKP-3 [MAPK (mitogen-activated protein kinase) phosphatase-3] specifically inactivates ERK1/2 (extracellular-signal-regulated kinase 1/2) in vitro and in vivo. DUSP6/MKP-3 is inducible by FGF (fibroblast growth factor) signalling and acts as a negative regulator of ERK activity in key and discrete signalling centres that direct outgrowth and patterning in early vertebrate embryos. However, the molecular mechanism by which FGFs, induce DUSP6/ MKP-3 expression and hence help to set ERK1/2 signalling levels is unknown. In the present study, we demonstrate, using pharmacological inhibitors and analysis of the murine DUSP6/ MKP-3 gene promoter, that the ERK pathway is critical for FGF-induced DUSP6/MKP-3 transcription. Furthermore, we show that this response is mediated by a conserved binding site for the Ets (E twenty-six) family of transcriptional regulators and that the Ets2 protein, a known target of ERK signalling, binds to the endogenous DUSP6/MKP-3 promoter. Finally, the murine DUSP6/MKP-3 promoter coupled to EGFP (enhanced green fluorescent protein) recapitulates the specific pattern of endogenous DUSP6/MKP-3 mRNA expression in the chicken neural plate, where its activity depends on FGFR (FGF receptor) and MAPK signalling and an intact Ets-binding site. These findings identify a conserved Ets-factor-dependent mechanism by which ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling.

    Original languageEnglish
    Pages (from-to)287-298
    Number of pages12
    JournalBiochemical Journal
    Volume412
    Issue number2
    DOIs
    Publication statusPublished - 1 Jun 2008

    Keywords

    • dual-specificity phosphatase 6 (DUSP6)
    • fibroblast growth factor (FGF)
    • mitogen-activated protein kinase (MAPK)
    • mitogen-activated protein kinase phosphatase-3 (MKP-3)
    • phosphatase
    • transcription
    • ACTIVATED PROTEIN-KINASE
    • DUAL-SPECIFICITY PHOSPHATASES
    • MAP-KINASE
    • CATALYTIC ACTIVATION
    • VERTEBRATE LIMB
    • IN-VIVO
    • EXPRESSION
    • MKP3
    • EMBRYO
    • FAMILY

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