PDK1, the master regulator of AGC kinase signal transduction

Semin Cell Dev Biol. 2004 Apr;15(2):161-70. doi: 10.1016/j.semcdb.2003.12.022.

Abstract

The interaction of insulin and growth factors with their receptors on the outside surface of a cell, leads to the activation of phosphatidylinositol 3-kinase (PI 3-kinase) and generation of the phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) second messenger at the inner surface of the cell membrane. One of the most studied signalling events controlled by PtdIns(3,4,5)P3, comprises the activation of a group of AGC family protein kinases, including isoforms of protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), serum- and glucocorticoid-induced protein kinase (SGK) and protein kinase C (PKC), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (PDK1), which phosphorylates and activates the AGC kinase members regulated by PI 3-kinase. We also discuss whether inhibitors of PDK1 might have chemotherapeutic potential in the treatment of cancers in which the PDK1-regulated AGC kinases are constitutively activated.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Humans
  • Immediate-Early Proteins
  • Neoplasms / metabolism
  • Nuclear Proteins*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction*

Substances

  • Immediate-Early Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • 3-Phosphoinositide-Dependent Protein Kinases
  • AKT1 protein, human
  • PDPK1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • serum-glucocorticoid regulated kinase