The regulation of oncogenic Ras/ERK signalling by dual-specificitymitogen activated protein kinase phosphatases (MKPs)

Andrew M. Kidger, Stephen M. Keyse (Lead / Corresponding author)

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    Abstract

    Dual-specificity MAP kinase (MAPK) phosphatases (MKPs or DUSPs) are well-established negative regulators of MAPK signalling in mammalian cells and tissues. By virtue of their differential subcellular localisation and ability to specifically recognise, dephosphorylate and inactivate different MAPK isoforms, they are key spatiotemporal regulators of pathway activity. Furthermore, as they are transcriptionally regulated as downstream targets of MAPK signalling they can either act as classical negative feedback regulators or mediate cross talk between distinct MAPK pathways. Because MAPKs and particularly Ras/ERK signalling are implicated in cancer initiation and development, the observation that MKPs are abnormally regulated in human tumours has been interpreted as evidence that these enzymes can either suppress or promote carcinogenesis. However, definitive evidence of such roles has been lacking. Here we review recent work based on the use of mouse models, biochemical studies and clinical data that demonstrate key roles for MKPs in modulating the oncogenic potential of Ras/ERK signalling and also indicate that these enzymes may play a role in the response of tumours to certain anticancer drugs. Overall, this work reinforces the importance of negative regulatory mechanisms in modulating the activity of oncogenic MAPK signalling and indicates that MKPs may provide novel targets for therapeutic intervention in cancer.
    Original languageEnglish
    Pages (from-to)125-132
    Number of pages8
    JournalSeminars in Cell & Developmental Biology
    Volume50
    Early online date11 Jan 2016
    DOIs
    Publication statusPublished - Feb 2016

    Fingerprint

    Phosphoprotein Phosphatases
    Protein Kinases
    Phosphotransferases
    Neoplasms
    Enzymes
    Phosphoric Monoester Hydrolases
    Protein Isoforms
    Carcinogenesis
    Pharmaceutical Preparations

    Keywords

    • MAP kinase
    • Extracellular signal-regulated kinase
    • MAP kinase phosphatase
    • DUAL-SPECIFICITY PHOSPHATASE
    • DUSP5
    • DUSP6/MKP-3
    • RAS ONCOGENE

    Cite this

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    title = "The regulation of oncogenic Ras/ERK signalling by dual-specificitymitogen activated protein kinase phosphatases (MKPs)",
    abstract = "Dual-specificity MAP kinase (MAPK) phosphatases (MKPs or DUSPs) are well-established negative regulators of MAPK signalling in mammalian cells and tissues. By virtue of their differential subcellular localisation and ability to specifically recognise, dephosphorylate and inactivate different MAPK isoforms, they are key spatiotemporal regulators of pathway activity. Furthermore, as they are transcriptionally regulated as downstream targets of MAPK signalling they can either act as classical negative feedback regulators or mediate cross talk between distinct MAPK pathways. Because MAPKs and particularly Ras/ERK signalling are implicated in cancer initiation and development, the observation that MKPs are abnormally regulated in human tumours has been interpreted as evidence that these enzymes can either suppress or promote carcinogenesis. However, definitive evidence of such roles has been lacking. Here we review recent work based on the use of mouse models, biochemical studies and clinical data that demonstrate key roles for MKPs in modulating the oncogenic potential of Ras/ERK signalling and also indicate that these enzymes may play a role in the response of tumours to certain anticancer drugs. Overall, this work reinforces the importance of negative regulatory mechanisms in modulating the activity of oncogenic MAPK signalling and indicates that MKPs may provide novel targets for therapeutic intervention in cancer.",
    keywords = "MAP kinase, Extracellular signal-regulated kinase , MAP kinase phosphatase, DUAL-SPECIFICITY PHOSPHATASE, DUSP5, DUSP6/MKP-3, RAS ONCOGENE",
    author = "Kidger, {Andrew M.} and Keyse, {Stephen M.}",
    note = "S.M.K is supported by a programme grant from Cancer Research UK(C8227/A12053).A.M.K. is supported by a Dundee Cancer Centre Studentship. The authors would like to thank Dr Jim Caunt (University of Bath) for critical reading of this manuscript.",
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    T1 - The regulation of oncogenic Ras/ERK signalling by dual-specificitymitogen activated protein kinase phosphatases (MKPs)

    AU - Kidger, Andrew M.

    AU - Keyse, Stephen M.

    N1 - S.M.K is supported by a programme grant from Cancer Research UK(C8227/A12053).A.M.K. is supported by a Dundee Cancer Centre Studentship. The authors would like to thank Dr Jim Caunt (University of Bath) for critical reading of this manuscript.

    PY - 2016/2

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    N2 - Dual-specificity MAP kinase (MAPK) phosphatases (MKPs or DUSPs) are well-established negative regulators of MAPK signalling in mammalian cells and tissues. By virtue of their differential subcellular localisation and ability to specifically recognise, dephosphorylate and inactivate different MAPK isoforms, they are key spatiotemporal regulators of pathway activity. Furthermore, as they are transcriptionally regulated as downstream targets of MAPK signalling they can either act as classical negative feedback regulators or mediate cross talk between distinct MAPK pathways. Because MAPKs and particularly Ras/ERK signalling are implicated in cancer initiation and development, the observation that MKPs are abnormally regulated in human tumours has been interpreted as evidence that these enzymes can either suppress or promote carcinogenesis. However, definitive evidence of such roles has been lacking. Here we review recent work based on the use of mouse models, biochemical studies and clinical data that demonstrate key roles for MKPs in modulating the oncogenic potential of Ras/ERK signalling and also indicate that these enzymes may play a role in the response of tumours to certain anticancer drugs. Overall, this work reinforces the importance of negative regulatory mechanisms in modulating the activity of oncogenic MAPK signalling and indicates that MKPs may provide novel targets for therapeutic intervention in cancer.

    AB - Dual-specificity MAP kinase (MAPK) phosphatases (MKPs or DUSPs) are well-established negative regulators of MAPK signalling in mammalian cells and tissues. By virtue of their differential subcellular localisation and ability to specifically recognise, dephosphorylate and inactivate different MAPK isoforms, they are key spatiotemporal regulators of pathway activity. Furthermore, as they are transcriptionally regulated as downstream targets of MAPK signalling they can either act as classical negative feedback regulators or mediate cross talk between distinct MAPK pathways. Because MAPKs and particularly Ras/ERK signalling are implicated in cancer initiation and development, the observation that MKPs are abnormally regulated in human tumours has been interpreted as evidence that these enzymes can either suppress or promote carcinogenesis. However, definitive evidence of such roles has been lacking. Here we review recent work based on the use of mouse models, biochemical studies and clinical data that demonstrate key roles for MKPs in modulating the oncogenic potential of Ras/ERK signalling and also indicate that these enzymes may play a role in the response of tumours to certain anticancer drugs. Overall, this work reinforces the importance of negative regulatory mechanisms in modulating the activity of oncogenic MAPK signalling and indicates that MKPs may provide novel targets for therapeutic intervention in cancer.

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    KW - Extracellular signal-regulated kinase

    KW - MAP kinase phosphatase

    KW - DUAL-SPECIFICITY PHOSPHATASE

    KW - DUSP5

    KW - DUSP6/MKP-3

    KW - RAS ONCOGENE

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    M3 - Article

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