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Regulation of kinase activity of 3-phosphoinositide-dependent protein kinase-1 by binding to 14-3-3.

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a central role in activating the protein kinase A, G, and C subfamily. In particular, PDK1 plays an important role in regulating the Akt survival pathway by phosphorylating Akt on Thr-308. PDK1 kinase activity was thought to be constitutively active; however, recent reports suggested that its activity is regulated by binding to other proteins, such as protein kinase C-related kinase-2 (PRK2), p90 ribosomal protein S6 kinase-2 (RSK2), and heat-shock protein 90 (Hsp90). Here we report that PDK1 binds to 14-3-3 proteins in vivo and in vitro through the sequence surrounding Ser-241, a residue that is phosphorylated by itself and is critical for its kinase activity. Mutation of PDK1 to increase its binding to 14-3-3 decreased its kinase activity in vivo. By contrast, mutation of PDK1 to decrease its interaction with 14-3-3 resulted in increased PDK1 kinase activity. Moreover, incubation of wild-type PDK1 with recombinant 14-3-3 in vitro decreased its kinase activity. These data indicate that PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241.

Pubmed ID: 12177059

Authors

  • Sato S
  • Fujita N
  • Tsuruo T

Journal

The Journal of biological chemistry

Publication Data

October 18, 2002

Associated Grants

None

Mesh Terms

  • 14-3-3 Proteins
  • 3-Phosphoinositide-Dependent Protein Kinases
  • 3T3 Cells
  • Animals
  • Binding Sites
  • Blotting, Western
  • COS Cells
  • Catalysis
  • Cell Line
  • DNA, Complementary
  • Down-Regulation
  • Gene Expression Regulation, Enzymologic
  • Genetic Vectors
  • Glutathione Transferase
  • HSP90 Heat-Shock Proteins
  • Humans
  • Mice
  • Mutagenesis, Site-Directed
  • Mutation
  • Peptides
  • Plasmids
  • Precipitin Tests
  • Protein Binding
  • Protein Isoforms
  • Protein Kinase C
  • Protein-Serine-Threonine Kinases
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Serine
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured
  • Tyrosine 3-Monooxygenase