Scaffolding function of PAK in the PDK1-Akt pathway

Nat Cell Biol. 2008 Nov;10(11):1356-64. doi: 10.1038/ncb1795. Epub 2008 Oct 19.

Abstract

Many extracellular signals stimulate phosphatidylinositol-3-kinase, which in turn activates the Rac1 GTPase, the protein kinase Akt and the Akt Thr 308 upstream kinase PDK1. Active Rac1 stimulates a number of events, including substrate phosphorylation by a subgroup of the PAK family of kinases. The combined effects of Rac1, PDK1 and Akt are crucial for cell migration, growth, survival, metabolism and tumorigenesis. Here we show that Rac1 stimulates a second, kinase-independent function of PAK1. The PAK1 kinase domain serves as a scaffold to facilitate Akt stimulation by PDK1 and to aid recruitment of Akt to the membrane. PAK differentially activates subpopulations of Akt. These findings reveal scaffolding functions of PAK that regulate the efficiency, localization and specificity of the PDK1-Akt pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Enzyme Activation
  • Fibroblasts / cytology
  • Glutathione Transferase / metabolism
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / pharmacology
  • Phosphorylation / drug effects
  • Plasmids
  • Protein Kinases / metabolism
  • Protein Kinases / pharmacology
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • RNA Interference
  • Rats
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects
  • Transfection
  • p21-Activated Kinases / chemistry
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / pharmacology

Substances

  • Pdk1 protein, mouse
  • Pdk1 protein, rat
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Recombinant Proteins
  • Glutathione Transferase
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein