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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters

Nabil Djouder1, Stefan Christian Metzler, Alexander Schmidt

  • 1Institute of Cell Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.

Molecular Cell
|October 16, 2007
PubMed

Insights

The study reveals that URI and protein phosphatase 1 gamma (PP1gamma) form mitochondrial complexes that regulate cell survival signaling. This pathway ensures apoptosis thresholds align with nutrient availability, opposing sustained survival signals.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • S6 kinase 1 (S6K1) is a key regulator of cell growth and survival, integrating nutrient and growth factor signals.
  • S6K1 phosphorylates and inactivates the proapoptotic molecule BAD, promoting cell survival.
  • Mitochondria play a crucial role in apoptosis and are a site for S6K1 activity.

Purpose of the Study:

  • To investigate the role of the prefoldin chaperone URI in S6K1-mediated cell survival.
  • To elucidate the mechanism by which S6K1 regulates mitochondrial pathways involved in apoptosis.
  • To identify novel components of the S6K1 signaling network at the mitochondria.

Main Methods:

  • Cell culture and treatment with growth factors or rapamycin.
  • Co-immunoprecipitation to detect protein complex formation.
  • Western blotting to assess protein phosphorylation and levels.
  • Enzyme activity assays for PP1gamma.

Main Results:

  • URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria in growth factor-deprived cells, inhibiting PP1gamma activity.
  • Growth factor stimulation causes S6K1-mediated phosphorylation of URI at serine 371, leading to the disassembly of URI/PP1gamma complexes.
  • Disassembly of these complexes activates a PP1gamma-dependent negative feedback loop, reducing S6K1 activity and BAD phosphorylation, thus altering the apoptosis threshold.

Conclusions:

  • URI and PP1gamma are integral components of an S6K1-regulated mitochondrial pathway.
  • This pathway opposes sustained S6K1 survival signaling and fine-tunes the mitochondrial apoptosis threshold based on nutrient and growth factor availability.
  • The findings reveal a novel feedback mechanism controlling cell survival and apoptosis.

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