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MSK1 activity is controlled by multiple phosphorylation sites

Claire E McCoy1, David G Campbell, Maria Deak

  • 1MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.

The Biochemical Journal
|December 1, 2004
PubMed

Insights

Mitogen- and stress-activated protein kinase 1 (MSK1) autophosphorylates on multiple sites, with key sites regulating its catalytic activity. MSK1 activation requires ERK1/2 or p38 MAPK cascades, unlike related RSK proteins.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Kinase signaling pathways

Background:

  • Mitogen- and stress-activated protein kinase 1 (MSK1) is activated downstream of ERK1/2 and p38 MAPK cascades.
  • Understanding MSK1 autophosphorylation is crucial for elucidating its regulatory mechanisms.

Purpose of the Study:

  • To investigate the autophosphorylation sites of MSK1.
  • To determine the role of specific phosphorylation sites in MSK1 catalytic activity.
  • To compare MSK1 activation requirements with related RSK proteins.

Main Methods:

  • Site-directed mutagenesis to identify and alter phosphorylation sites.
  • In vitro kinase assays to assess MSK1 catalytic activity.
  • Analysis of MSK1 phosphorylation patterns.

Main Results:

  • MSK1 autophosphorylates on at least six sites.
  • Phosphorylation of Ser-212 and Ser-376 by the C-terminal kinase domain is essential for N-terminal kinase domain activity.
  • Mutation of Ser-381 decreases MSK1 activity, potentially by inhibiting Ser-376 phosphorylation.
  • MSK1 activation depends on ERK1/2 or p38 MAPK, without additional inputs like PDK1.

Conclusions:

  • MSK1 possesses multiple autophosphorylation sites that regulate its kinase activity.
  • The activation of MSK1 is primarily controlled by upstream MAPK pathways.
  • MSK1 activation differs from RSK proteins, which require PDK1 phosphorylation.

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