MSK1 activity is controlled by multiple phosphorylation sites

Claire E. McCoy, David G. Campbell, Maria Deak, Graham B. Bloomberg, J. Simon C. Arthur

    Research output: Contribution to journalArticle

    124 Citations (Scopus)

    Abstract

    MSK1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the ERK1/2 (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 and therefore for the phosphorylation of MSK1 substrates in vitro. Ser-381 is also phosphorylated by the C-terminal kinase domain, and mutation of Ser-381 decreases MSK1 activity, probably through the inhibition of Ser-376 phosphorylation. Ser-750, Ser-752 and Ser-758 are phosphorylated by the N-terminal kinase domain; however, their function is not known. The activation of MSK1 in cells therefore requires the activation of the ERK1/2 or p38 MAPK cascades and does not appear to require additional signalling inputs. This is in contrast with the closely related RSK (p90 ribosomal S6 kinase) proteins, whose activity requires phosphorylation by PDK1 (3-phosphoinositide-dependent protein kinase 1) in addition to phosphorylation by ERK1/2.

    Original languageEnglish
    Pages (from-to)507-517
    Number of pages11
    JournalBiochemical Journal
    Volume387
    Issue numberPt 2
    DOIs
    Publication statusPublished - 15 Apr 2005

    Fingerprint

    Phosphorylation
    Phosphotransferases
    p38 Mitogen-Activated Protein Kinases
    3-Phosphoinositide-Dependent Protein Kinases
    90-kDa Ribosomal Protein S6 Kinases
    Chemical activation
    Mitogen-Activated Protein Kinase 1
    Heat-Shock Proteins
    Mitogen-Activated Protein Kinases
    Mitogens
    Protein Kinases
    Catalyst activity
    Mutation
    Substrates
    Proteins

    Keywords

    • Animals
    • Enzyme Activation
    • Humans
    • Amino Acid Sequence
    • Mutagenesis, Site-Directed
    • p38 Mitogen-Activated Protein Kinases
    • Phosphorylation
    • Ribosomal Protein S6 Kinases, 90-kDa
    • Molecular Sequence Data
    • Mitogen-Activated Protein Kinase 3
    • Mitogens
    • Mitogen-Activated Protein Kinase 1
    • Cell Line

    Cite this

    McCoy, Claire E. ; Campbell, David G. ; Deak, Maria ; Bloomberg, Graham B. ; Arthur, J. Simon C. / MSK1 activity is controlled by multiple phosphorylation sites. In: Biochemical Journal. 2005 ; Vol. 387, No. Pt 2. pp. 507-517.
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    abstract = "MSK1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the ERK1/2 (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 and therefore for the phosphorylation of MSK1 substrates in vitro. Ser-381 is also phosphorylated by the C-terminal kinase domain, and mutation of Ser-381 decreases MSK1 activity, probably through the inhibition of Ser-376 phosphorylation. Ser-750, Ser-752 and Ser-758 are phosphorylated by the N-terminal kinase domain; however, their function is not known. The activation of MSK1 in cells therefore requires the activation of the ERK1/2 or p38 MAPK cascades and does not appear to require additional signalling inputs. This is in contrast with the closely related RSK (p90 ribosomal S6 kinase) proteins, whose activity requires phosphorylation by PDK1 (3-phosphoinositide-dependent protein kinase 1) in addition to phosphorylation by ERK1/2.",
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    MSK1 activity is controlled by multiple phosphorylation sites. / McCoy, Claire E.; Campbell, David G.; Deak, Maria; Bloomberg, Graham B.; Arthur, J. Simon C.

    In: Biochemical Journal, Vol. 387, No. Pt 2, 15.04.2005, p. 507-517.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - MSK1 activity is controlled by multiple phosphorylation sites

    AU - McCoy, Claire E.

    AU - Campbell, David G.

    AU - Deak, Maria

    AU - Bloomberg, Graham B.

    AU - Arthur, J. Simon C.

    PY - 2005/4/15

    Y1 - 2005/4/15

    N2 - MSK1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the ERK1/2 (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 and therefore for the phosphorylation of MSK1 substrates in vitro. Ser-381 is also phosphorylated by the C-terminal kinase domain, and mutation of Ser-381 decreases MSK1 activity, probably through the inhibition of Ser-376 phosphorylation. Ser-750, Ser-752 and Ser-758 are phosphorylated by the N-terminal kinase domain; however, their function is not known. The activation of MSK1 in cells therefore requires the activation of the ERK1/2 or p38 MAPK cascades and does not appear to require additional signalling inputs. This is in contrast with the closely related RSK (p90 ribosomal S6 kinase) proteins, whose activity requires phosphorylation by PDK1 (3-phosphoinositide-dependent protein kinase 1) in addition to phosphorylation by ERK1/2.

    AB - MSK1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the ERK1/2 (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 and therefore for the phosphorylation of MSK1 substrates in vitro. Ser-381 is also phosphorylated by the C-terminal kinase domain, and mutation of Ser-381 decreases MSK1 activity, probably through the inhibition of Ser-376 phosphorylation. Ser-750, Ser-752 and Ser-758 are phosphorylated by the N-terminal kinase domain; however, their function is not known. The activation of MSK1 in cells therefore requires the activation of the ERK1/2 or p38 MAPK cascades and does not appear to require additional signalling inputs. This is in contrast with the closely related RSK (p90 ribosomal S6 kinase) proteins, whose activity requires phosphorylation by PDK1 (3-phosphoinositide-dependent protein kinase 1) in addition to phosphorylation by ERK1/2.

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    KW - Humans

    KW - Amino Acid Sequence

    KW - Mutagenesis, Site-Directed

    KW - p38 Mitogen-Activated Protein Kinases

    KW - Phosphorylation

    KW - Ribosomal Protein S6 Kinases, 90-kDa

    KW - Molecular Sequence Data

    KW - Mitogen-Activated Protein Kinase 3

    KW - Mitogens

    KW - Mitogen-Activated Protein Kinase 1

    KW - Cell Line

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    JO - Biochemical Journal

    JF - Biochemical Journal

    SN - 0264-6021

    IS - Pt 2

    ER -