Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62

Margaret J. Stafford, Nick A. Morrice, Mark W. Peggie, Philip Cohen

    Research output: Contribution to journalArticle

    31 Citations (Scopus)

    Abstract

    The protein kinase COT/Tpl2 is activated by interleukin-1 (IL-1), TNFα and lipopolysaccharide, and its activation by these agonists involves the IκB kinase β (IKKβ) catalysed phosphorylation of the p105 regulatory subunit. Here, we show that COT activation also requires catalytic subunit phosphorylation, since IL-1β induced a 5-10-fold activation of a COT mutant unable to bind p105. Activation was paralleled by the phosphorylation of Thr290 and Ser62 and unaffected by the IKKβ inhibitor PS1145 at concentrations which prevented the degradation of IκBα. Mutagenesis experiments indicated that COT activation is initiated by Thr290 phosphorylation catalysed by an IL-1-stimulated protein kinase distinct from IKKβ, while Ser62 phosphorylation is an autophosphorylation event required for maximal activation.

    Original languageEnglish
    Pages (from-to)4010-4014
    Number of pages5
    JournalFEBS Letters
    Volume580
    Issue number16
    DOIs
    Publication statusPublished - 10 Jul 2006

    Fingerprint

    Phosphorylation
    Interleukin-1
    Catalytic Domain
    Chemical activation
    Protein Kinases
    Mutagenesis
    Corrosion inhibitors
    Lipopolysaccharides
    Phosphotransferases
    Degradation
    Experiments

    Keywords

    • COT
    • IKK
    • Interleukin-1
    • MAP kinase
    • Proinflammatory cytokine

    Cite this

    Stafford, Margaret J. ; Morrice, Nick A. ; Peggie, Mark W. ; Cohen, Philip. / Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62. In: FEBS Letters. 2006 ; Vol. 580, No. 16. pp. 4010-4014.
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    abstract = "The protein kinase COT/Tpl2 is activated by interleukin-1 (IL-1), TNFα and lipopolysaccharide, and its activation by these agonists involves the IκB kinase β (IKKβ) catalysed phosphorylation of the p105 regulatory subunit. Here, we show that COT activation also requires catalytic subunit phosphorylation, since IL-1β induced a 5-10-fold activation of a COT mutant unable to bind p105. Activation was paralleled by the phosphorylation of Thr290 and Ser62 and unaffected by the IKKβ inhibitor PS1145 at concentrations which prevented the degradation of IκBα. Mutagenesis experiments indicated that COT activation is initiated by Thr290 phosphorylation catalysed by an IL-1-stimulated protein kinase distinct from IKKβ, while Ser62 phosphorylation is an autophosphorylation event required for maximal activation.",
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    Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62. / Stafford, Margaret J.; Morrice, Nick A.; Peggie, Mark W.; Cohen, Philip.

    In: FEBS Letters, Vol. 580, No. 16, 10.07.2006, p. 4010-4014.

    Research output: Contribution to journalArticle

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    AU - Stafford, Margaret J.

    AU - Morrice, Nick A.

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    AB - The protein kinase COT/Tpl2 is activated by interleukin-1 (IL-1), TNFα and lipopolysaccharide, and its activation by these agonists involves the IκB kinase β (IKKβ) catalysed phosphorylation of the p105 regulatory subunit. Here, we show that COT activation also requires catalytic subunit phosphorylation, since IL-1β induced a 5-10-fold activation of a COT mutant unable to bind p105. Activation was paralleled by the phosphorylation of Thr290 and Ser62 and unaffected by the IKKβ inhibitor PS1145 at concentrations which prevented the degradation of IκBα. Mutagenesis experiments indicated that COT activation is initiated by Thr290 phosphorylation catalysed by an IL-1-stimulated protein kinase distinct from IKKβ, while Ser62 phosphorylation is an autophosphorylation event required for maximal activation.

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