NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling

Nature. 1999 Sep 2;401(6748):86-90. doi: 10.1038/43474.

Abstract

The mechanisms of cell proliferation and transformation are intrinsically linked to the process of apoptosis: the default of proliferating cells is to die unless specific survival signals are provided. Platelet-derived growth factor (PDGF) is a principal survival factor that inhibits apoptosis and promotes proliferation, but the mechanisms mediating its anti-apoptotic properties are not completely understood. Here we show that the transcription factor NF-kappaB is important in PDGF signalling. NF-kappaB transmits two signals: one is required for the induction of proto-oncogene c-myc and proliferation, and the second, an anti-apoptotic signal, counterbalances c-Myc cytotoxicity. We have traced a putative pathway whereby PDGF activates NF-kappaB through Ras and phospatidylinositol-3-kinase (PI(3)K) to the PKB/Akt protein kinase and the IkappaB kinase (IKK); NF-kappaB thus appears to be a target of the anti-apoptotic Ras/PI(3)K/Akt pathway. We show that, upon PDGF stimulation, Akt transiently associates in vivo with IKK and induces IKK activation. These findings establish a role for NF-kappaB in growth factor signalling and define an anti-apoptotic Ras/PI(3)K/Akt/IKK/NF-kappaB pathway, thus linking anti-apoptotic signalling with transcription machinery.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis*
  • Catalysis
  • Cell Division / physiology
  • Cells, Cultured
  • DNA / metabolism
  • Gene Expression Regulation
  • Humans
  • I-kappa B Kinase
  • Mice
  • Mitogens / metabolism
  • Mitogens / physiology
  • Mutation
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Platelet-Derived Growth Factor / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-myc / metabolism
  • Rats
  • Recombinant Proteins / metabolism
  • Signal Transduction*
  • Transfection
  • ras Proteins / metabolism

Substances

  • Mitogens
  • NF-kappa B
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Recombinant Proteins
  • DNA
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • ras Proteins