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)

    Research output: Contribution to journalArticle

    124 Citations (Scopus)

    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

    Cite this

    Ekerot, Maria ; Stavridis, Marios P. ; Delavaine, Laurent ; Mitchell, Michael P. ; Staples, Christopher ; Owens, David M. ; Keenan, Iain D. ; Dickinson, Robin J. ; Storey, Kate G. ; Keyse, Stephen M. / 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. In: Biochemical Journal. 2008 ; Vol. 412, No. 2. pp. 287-298.
    @article{a1920e12b2954a13bccd08b3ff372776,
    title = "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",
    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.",
    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",
    author = "Maria Ekerot and Stavridis, {Marios P.} and Laurent Delavaine and Mitchell, {Michael P.} and Christopher Staples and Owens, {David M.} and Keenan, {Iain D.} and Dickinson, {Robin J.} and Storey, {Kate G.} and Keyse, {Stephen M.}",
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    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. / Ekerot, Maria; Stavridis, Marios P.; Delavaine, Laurent; Mitchell, Michael P.; Staples, Christopher; Owens, David M.; Keenan, Iain D.; Dickinson, Robin J.; Storey, Kate G.; Keyse, Stephen M. (Lead / Corresponding author).

    In: Biochemical Journal, Vol. 412, No. 2, 01.06.2008, p. 287-298.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - 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

    AU - Ekerot, Maria

    AU - Stavridis, Marios P.

    AU - Delavaine, Laurent

    AU - Mitchell, Michael P.

    AU - Staples, Christopher

    AU - Owens, David M.

    AU - Keenan, Iain D.

    AU - Dickinson, Robin J.

    AU - Storey, Kate G.

    AU - Keyse, Stephen M.

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    N2 - 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.

    AB - 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.

    KW - dual-specificity phosphatase 6 (DUSP6)

    KW - fibroblast growth factor (FGF)

    KW - mitogen-activated protein kinase (MAPK)

    KW - mitogen-activated protein kinase phosphatase-3 (MKP-3)

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    KW - DUAL-SPECIFICITY PHOSPHATASES

    KW - MAP-KINASE

    KW - CATALYTIC ACTIVATION

    KW - VERTEBRATE LIMB

    KW - IN-VIVO

    KW - EXPRESSION

    KW - MKP3

    KW - EMBRYO

    KW - FAMILY

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    U2 - 10.1042/BJ20071512

    DO - 10.1042/BJ20071512

    M3 - Article

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    JF - Biochemical Journal

    SN - 0264-6021

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