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A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1.

The 90 kDa ribosomal S6 kinase-2 (RSK2) is a growth factor-stimulated protein kinase with two kinase domains. The C-terminal kinase of RSK2 is activated by ERK-type MAP kinases, leading to autophosphorylation of RSK2 at Ser386 in a hydrophobic motif. The N-terminal kinase is activated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) through phosphorylation of Ser227, and phosphorylates the substrates of RSK. Here, we identify Ser386 in the hydrophobic motif of RSK2 as a phosphorylation-dependent docking site and activator of PDK1. Treatment of cells with growth factor induced recruitment of PDK1 to the Ser386-phosphorylated hydrophobic motif and phosphorylation of RSK2 at Ser227. A RSK2-S386K mutant showed no interaction with PDK1 or phosphorylation at Ser227. Interaction with Ser386-phosphorylated RSK2 induced autophosphorylation of PDK1. Addition of a synthetic phosphoSer386 peptide (RSK2(373-396)) increased PDK1 activity 6-fold in vitro. Finally, mutants of RSK2 and MSK1, a RSK-related kinase, with increased affinity for PDK1, were constitutively active in vivo and phosphorylated histone H3. Our results suggest a novel regulatory mechanism based on phosphoserine-mediated recruitment of PDK1 to RSK2, leading to coordinated phosphorylation and activation of PDK1 and RSK2.

Pubmed ID: 10856237


  • Frödin M
  • Jensen CJ
  • Merienne K
  • Gammeltoft S


The EMBO journal

Publication Data

June 15, 2000

Associated Grants


Mesh Terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Binding Sites
  • Catalysis
  • Enzyme Activation
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinases
  • Models, Biological
  • Mutation
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Serine