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

J A Romashkova1, S S Makarov

  • 1Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, 27599-7280, USA.

Nature
|September 15, 1999
PubMed

Insights

Platelet-derived growth factor (PDGF) promotes cell survival by inhibiting apoptosis. This study reveals PDGF activates NF-kappaB via the Ras/PI(3)K/Akt/IKK pathway, linking survival signals to cell proliferation control.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Cell proliferation and transformation are closely tied to apoptosis, the programmed cell death pathway.
  • Platelet-derived growth factor (PDGF) is a key survival factor promoting cell proliferation but its anti-apoptotic mechanisms are not fully elucidated.
  • Understanding how survival signals regulate cell fate is crucial for cancer research.

Purpose of the Study:

  • To investigate the role of the transcription factor NF-kappaB in PDGF signaling.
  • To elucidate the molecular pathway mediating PDGF's anti-apoptotic effects.
  • To link growth factor signaling with the transcription machinery controlling cell fate.

Main Methods:

  • Investigated PDGF-induced activation of NF-kappaB.
  • Utilized Ras, phosphatidylinositol-3-kinase (PI(3)K), PKB/Akt, and IkappaB kinase (IKK) as key components in the signaling pathway.
  • Examined in vivo association of Akt with IKK upon PDGF stimulation.

Main Results:

  • Demonstrated NF-kappaB's critical role in PDGF signaling.
  • Identified NF-kappaB as a mediator of both proliferation (via c-myc) and anti-apoptotic signals.
  • Showed that PDGF activates NF-kappaB through a Ras/PI(3)K/Akt/IKK pathway.
  • Confirmed Akt's transient in vivo association with and activation of IKK following PDGF stimulation.

Conclusions:

  • Established a novel anti-apoptotic signaling pathway: Ras/PI(3)K/Akt/IKK/NF-kappaB.
  • Linked PDGF-mediated survival signals directly to the transcriptional machinery.
  • Provided new insights into the molecular mechanisms governing cell proliferation, survival, and the inhibition of apoptosis.

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