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Target of Rapamycin Complex 2 Regulates Actin Polarization and Endocytosis via Multiple Pathways

Delphine Rispal1, Sandra Eltschinger1, Michael Stahl1

  • 1From the Department of Molecular Biology and Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, 1211 Geneva.

The Journal of Biological Chemistry
|April 18, 2015
PubMed

Insights

Target of rapamycin complex 2 (TORC2) regulates cell functions through distinct rapid and slow pathways. Rapid signaling involves protein phosphorylation, while slow signaling alters plasma membrane tension via sphingolipid depletion.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Target of rapamycin (TOR) is a crucial kinase regulating cell growth and metabolism.
  • TOR operates in two complexes: TORC1 and TORC2, with TORC2 being less understood and rapamycin-insensitive.
  • TORC2 depletion affects actin polarization and endocytosis, but the underlying mechanisms are unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TORC2 regulates actin polarization and endocytosis.
  • To differentiate the rapid and slow signaling pathways controlled by TORC2.

Main Methods:

  • Engineered a yeast strain for acute and specific inhibition of TORC2 using NVP-BHS345.
  • Performed kinetic analyses following TORC2 inhibition.
  • Utilized quantitative phosphoproteomics to identify signaling events.

Main Results:

  • TORC2 regulates actin polarization and endocytosis through distinct rapid and slow pathways.
  • Rapid signaling is mediated by phospholipid flippase kinases Fpk1 and Fpk2.
  • Slow signaling involves increased plasma membrane tension due to sphingolipid depletion.

Conclusions:

  • TORC2 employs dual signaling mechanisms: rapid phosphorylation cascades and slow membrane tension changes.
  • These findings reveal intricate control of cell physiology by TORC2.
  • Highlights the role of Fpk1/Fpk2 and sphingolipids in TORC2-mediated cellular processes.
Keywords:
cell signalinglipid signalingphosphoproteomeplasma membraneprotein kinasetarget of rapamycin (TOR)target of rapamycin complex 2, Ypk1, sphingolipids, actin polarization, endocytosis, flippase kinase

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