title: ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate.
abstract: Insufficient nutrients disrupt physiological homeostasis, resulting in diseases and even death. Considering the physiological and pathological consequences of this metabolic stress, the adaptive responses that cells utilize under this condition are of great interest. We show that under low-glucose conditions, cells initiate adaptation followed by apoptosis responses using PERK/Akt and MEK1/ERK2 signaling, respectively. For adaptation, cells engage the ER stress-induced unfolded protein response, which results in PERK/Akt activation and cell survival. Sustained and extreme energetic stress promotes a switch to isoform-specific MEK1/ERK2 signaling, induction of GCN2/eIF2α phosphorylation, and ATF4 expression, which overrides PERK/Akt-mediated adaptation and induces apoptosis through ATF4-dependent expression of pro-apoptotic factors including Bid and Trb3. ERK2 activation during metabolic stress contributes to changes in TCA cycle and amino acid metabolism, and cell death, which is suppressed by glutamate and α-ketoglutarate supplementation. Taken together, our results reveal promising targets to protect cells or tissues from metabolic stress.
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sejeong
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gwen R
authors.initials: GR
authors.lastname: Buel
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Wolgamott
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Plas
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: job2064@med.cornell.edu.
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: say2008@med.cornell.edu.
authors.forename: Sang-Oh
authors.initials: SO
authors.lastname: Yoon
mesh_terms: D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D007656:Ketoglutaric Acids; D018698:Glutamic Acid; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D005947:Glucose