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

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 accumulation. Specifically, we find that TORC2-Ypk1 regulates actin polarization both by vacuole-related controlled by the phospholipid flippase kinase Fpk1 and sphingolipids, and by mitochondria-mediated duanyu1670, controlled by the 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 duanyu1670, 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 as regulators of actin and suggest that duanyu1670 may play an important role in mTORC2-dependent dysregulation of the actin cytoskeleton in cancer cells.

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