Nitrogen regulates AMPK to control TORC1 signaling

Curr Biol. 2015 Feb 16;25(4):445-54. doi: 10.1016/j.cub.2014.12.034. Epub 2015 Jan 29.


Background: Cell growth and cell-cycle progression are tightly coordinated to enable cells to adjust their size (timing of division) to the demands of proliferation in varying nutritional environments. In fission yeast, nitrogen stress results in sustained proliferation at a reduced size.

Results: Here, we show that cells can sense nitrogen stress to reduce target of rapamycin complex-1 (TORC1) activity. Nitrogen-stress-induced TORC1 inhibition differs from amino-acid-dependent control of TORC1 and requires the Ssp2 (AMPKα) kinase, the Tsc1/2 complex, and Rhb1 GTPase. Importantly, the β and γ regulatory subunits of AMPK are not required to control cell division in response to nitrogen stress, providing evidence for a nitrogen-sensing mechanism that is independent of changes in intracellular ATP/AMP levels. The CaMKK homolog Ssp1 is constitutively required for phosphorylation of the AMPKα(Ssp2) T loop. However, we find that a second homolog CaMKK(Ppk34) is specifically required to stimulate AMPKα(Ssp2) activation in response to nitrogen stress. Finally, ammonia also controls mTORC1 activity in human cells; mTORC1 is activated upon the addition of ammonium to glutamine-starved Hep3B cancer cells.

Conclusions: The alternative nitrogen source ammonia can simulate TORC1 activity to support growth and division under challenging nutrient settings, a situation often seen in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / genetics*
  • Multiprotein Complexes / metabolism
  • Nitrogen / metabolism*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Schizosaccharomyces / enzymology
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / physiology*
  • Schizosaccharomyces pombe Proteins / genetics*
  • Schizosaccharomyces pombe Proteins / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism


  • Multiprotein Complexes
  • Schizosaccharomyces pombe Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Serine-Threonine Kinases
  • Ssp2 protein, S pombe
  • TOR Serine-Threonine Kinases
  • Nitrogen