TSC2 mediates hyperosmotic stress-induced inactivation of mTORC1.
mTOR complex 1 (mTORC1) regulates cell growth and metabolism. mTORC1 activity is regulated via integration of positive growth-promoting stimuli and negative stress stimuli. One stress cells confront in physiological and pathophysiological contexts is hyperosmotic stress. The mechanism by which hyperosmotic stress regulates mTORC1 activity is not well understood. We show here that mild hyperosmotic stress induces a rapid and reversible inactivation of mTORC1 via a mechanism involving multiple upstream signaling pathways. We find that hyperosmotic stress causes dynamic changes in TSC2 phosphorylation by upstream kinases, such as Akt, thereby recruiting TSC2 from the cytoplasm to lysosomes where it acts on Rheb, the direct activator of mTORC1. This work puts together a signaling pathway whereby hyperosmotic stress inactivates mTORC1.
Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Monika
M
Plescher
Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Aurelio A
AA
Teleman
Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Constantinos
C
Demetriades
D000818:Animals; D002460:Cell Line; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008387:Marine Toxins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009997:Osmotic Pressure; D010080:Oxazoles / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D008387:Marine Toxins; D046912:Multiprotein Complexes; D010080:Oxazoles; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C059041:calyculin A; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D020559:Monomeric GTP-Binding Proteins