TOR complex 2-Ypk1 signaling regulates actin polarization via reactive oxygen species

Brad J. Niles, Ted Powers

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The evolutionarily conserved mTOR complex 2 (mTORC2) signaling pathway is an important regulator of actin cytoskeletal architecture and, as such, is a candidate target for preventing cancer cell motility and invasion. Remarkably, the precise mechanism(s) by which mTORC2 regulates the actin cytoskeleton have remained elusive. Here we show that in budding yeast, TORC2 and its downstream kinase Ypk1 regulate actin polarization by controlling reactive oxygen species (ROS) accumulation. Specifically, we find that TORC2-Ypk1 regulates actin polarization both by vacuole-related ROS, controlled by the phospholipid flippase kinase Fpk1 and sphingolipids, and by mitochondria-mediated ROS, controlled by the PKA subunit Tpk3. In addition, we find that the protein kinase C (Pkc1)/MAPK cascade, a well-established regulator of actin, acts downstream of Ypk1 to regulate ROS, in part by promoting degradation of the oxidative stress responsive repressor, cyclin C. Furthermore, we show that Ypk1 regulates Pkc1 activity through proper localization of Rom2 at the plasma membrane, which is also dependent on Fpk1 and sphingolipids. Together these findings demonstrate important links between TORC2/Ypk1 signaling, Fpk1, sphingolipids, Pkc1, and ROS as regulators of actin and suggest that ROS may play an important role in mTORC2-dependent dysregulation of the actin cytoskeleton in cancer cells.

Original languageEnglish (US)
Pages (from-to)3962-3972
Number of pages11
JournalMolecular Biology of the Cell
Volume25
Issue number24
DOIs
StatePublished - Dec 1 2014

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Actins
Reactive Oxygen Species
Sphingolipids
Actin Cytoskeleton
Cyclin C
Phosphotransferases
Saccharomycetales
Vacuoles
Protein Kinase C
Cell Movement
TOR complex 2
Neoplasms
Phospholipids
Mitochondria
Oxidative Stress
Cell Membrane

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

TOR complex 2-Ypk1 signaling regulates actin polarization via reactive oxygen species. / Niles, Brad J.; Powers, Ted.

In: Molecular Biology of the Cell, Vol. 25, No. 24, 01.12.2014, p. 3962-3972.

Research output: Contribution to journalArticle

Niles, Brad J. ; Powers, Ted. / TOR complex 2-Ypk1 signaling regulates actin polarization via reactive oxygen species. In: Molecular Biology of the Cell. 2014 ; Vol. 25, No. 24. pp. 3962-3972.
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