Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2

Genes Dev. 2018 Dec 1;32(23-24):1576-1590. doi: 10.1101/gad.318709.118. Epub 2018 Nov 26.


Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogen-activated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacceptor sites in a Slt2-dependent manner and diminished TORC2-mediated phosphorylation of its major downstream effector, protein kinase Ypk1. Deletion of Avo2 or expression of a phosphomimetic Avo2 allele rendered cells sensitive to two stresses (myriocin treatment and elevated exogenous acetic acid) that the cell requires Ypk1 activation by TORC2 to survive. Thus, Avo2 is necessary for optimal TORC2 activity, and Slt2-mediated phosphorylation of Avo2 down-regulates TORC2 signaling. Compared with wild-type Avo2, phosphomimetic Avo2 shows significant displacement from the plasma membrane, suggesting that Slt2 inhibits TORC2 by promoting Avo2 dissociation. Our findings are the first demonstration that TORC2 function is regulated by MAPK-mediated phosphorylation.

Keywords: mutants; protein kinase; regulation; signal transduction; yeast.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetic Acid / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Membrane / metabolism
  • Down-Regulation* / drug effects
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Fatty Acids, Monounsaturated / pharmacology
  • Gene Deletion
  • Glycogen Synthase Kinase 3 / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / genetics*
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Stress, Physiological / genetics*


  • Avo2 protein, S cerevisiae
  • Carrier Proteins
  • Fatty Acids, Monounsaturated
  • Saccharomyces cerevisiae Proteins
  • Mechanistic Target of Rapamycin Complex 2
  • Mitogen-Activated Protein Kinases
  • SLT2 protein, S cerevisiae
  • Glycogen Synthase Kinase 3
  • MCK1 protein, S cerevisiae
  • Acetic Acid
  • thermozymocidin