Regulation of protein kinase C zeta by PI 3-kinase and PDK-1

Curr Biol. 1998 Sep 24;8(19):1069-77. doi: 10.1016/s0960-9822(98)70444-0.

Abstract

Background: Protein kinase C zeta (PKC zeta) is a member of the PKC family of enzymes and is involved in a wide range of physiological processes including mitogenesis, protein synthesis, cell survival and transcriptional regulation. PKC zeta has received considerable attention recently as a target of phosphoinositide 3-kinase (PI 3-kinase), although the mechanism of PKC zeta activation is, as yet, unknown. Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (PDK-1), which binds with high affinity to the PI 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (Ptdins-3,4,5-P3), phosphorylates and potently activates two other PI 3-kinase targets, the protein kinases Akt/PKB and p70S6K. We therefore investigated whether PDK-1 is the kinase that activates PKC zeta.

Results: In vivo, PI 3-kinase is both necessary and sufficient to activate PKC zeta. PDK-1 phosphorylates and activates PKC zeta in vivo, and we have shown that this is due to phosphorylation of threonine 410 in the PKC zeta activation loop. In vitro, PDK-1 phosphorylates and activates PKC zeta in a Ptdins-3,4,5-P3-enhanced manner. PKC zeta and PDK-1 are associated in vivo, and membrane targeting of PKC zeta renders it constitutively active in cells.

Conclusions: Our results have identified PDK-1 as the kinase that phosphorylates and activates PKC zeta in the PI 3-kinase signaling pathway. This phosphorylation and activation of PKC zeta by PDK-1 is enhanced in the presence of Ptdins-3,4-5-P3. Consistent with the notion that PKCs are enzymes that are regulated at the plasma membrane, a membrane-targeted PKC zeta is constitutively active in the absence of agonist stimulation. The association between PKC zeta and PDK-1 reveals extensive cross-talk between enzymes in the PI 3-kinase signaling pathway.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • 3T3 Cells
  • Animals
  • Cell Line
  • Enzyme Activation
  • Mice
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphorylation
  • Phosphothreonine / metabolism
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / physiology*
  • Recombinant Fusion Proteins / metabolism
  • Transfection

Substances

  • Recombinant Fusion Proteins
  • Phosphothreonine
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • protein kinase C zeta
  • Protein Kinase C