title: mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress.
abstract: The mTOR nucleates two complexes, namely mTOR complex 1 and 2 (mTORC1 and mTORC2), which are implicated in cell growth, survival, metabolism, and cancer. Phosphorylation of the α-subunit of translation initiation factor eIF2 at serine 51 (eIF2αS51P) is a key event of mRNA translation initiation and a master regulator of cell fate during cellular stress. Recent studies have implicated mTOR signaling in the stress response, but its connection to eIF2αS51P has remained unclear. Herein, we report that genetic as well as catalytic inhibition of mTORC2 induces eIF2αS51P. On the other hand, the allosteric inhibitor rapamycin induces eIF2αS51P through pathways that are independent of mTORC1 inactivation. Increased eIF2αS51P by impaired mTORC2 depends on the inactivation of AKT, which primes the activation of the endoplasmic reticulum (ER)-resident kinase PERK/PEK. The biologic function of eIF2αS51P was characterized in tuberous sclerosis complex (TSC)-mutant cells, which are defective in mTORC2 and AKT activity. TSC-mutant cells exhibit increased PERK activity, which is downregulated by the reconstitution of the cells with an activated form of AKT1. Also, TSC-mutant cells are increasingly susceptible to ER stress, which is reversed by AKT1 reconstitution. The susceptibility of TSC-mutant cells to ER stress is further enhanced by the pharmacologic inhibition of PERK or genetic inactivation of eIF2αS51P. Thus, the PERK/eIF2αS51P arm is an important compensatory prosurvival mechanism, which substitutes for the loss of AKT under ER stress.
  
  
  CONCLUSIONS
  A novel mechanistic link between mTOR function and protein synthesis is identified in TSC-null tumor cells under stress and reveals potential for the development of antitumor treatments with stress-inducing chemotherapeutics.
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Clara
authors.initials: C
authors.lastname: Tenkerian
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Jothilatha
authors.initials: J
authors.lastname: Krishnamoorthy
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Zineb
authors.initials: Z
authors.lastname: Mounir
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Kazimierczak
authors.affiliation: Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.affiliation: Oncology Research Division, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Staschke
authors.affiliation: Department of Critical Care, McGill University Health Centre and Meakins-Christie Laboratories, Montreal, Quebec, Canada. Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Kristof
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Nutrition, School of Medicine, Case Western University, Cleveland, Ohio.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. antonis.koromilas@mcgill.ca.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase