title: Protein tyrosine phosphatase 1B deficiency potentiates PERK/eIF2α signaling in brown adipocytes.
abstract: BACKGROUND
  Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and body mass, and has been implicated in endoplasmic reticulum (ER) stress. Herein, we assess the role of PTP1B in ER stress in brown adipocytes, which are key regulators of thermogenesis and metabolic response.
  
  
  RESULTS
  To determine the role of PTP1B in ER stress, we utilized brown adipose tissue (BAT) from mice with adipose-specific PTP1B deletion, and brown adipocytes deficient in PTP1B and reconstituted with PTP1B wild type (WT) or the substrate-trapping PTP1B D181A (D/A) mutant. PTP1B deficiency led to upregulation of PERK-eIF2α phosphorylation and IRE1α-XBP1 sub-arms of the unfolded protein response. In addition, PTP1B deficiency sensitized differentiated brown adipocytes to chemical-induced ER stress. Moreover, PERK activation and tyrosine phosphorylation were increased in BAT and adipocytes lacking PTP1B. Increased PERK activity resulted in the induction of eIF2α phosphorylation at Ser51 and better translatability of ATF4 mRNA in response to ER stress. At the molecular level, we demonstrate direct interaction between PTP1B and PERK and identify PERK Tyr615 as a mediator of this association.
  
  
  CONCLUSIONS
  Collectively, the data demonstrate that PTP1B is a physiologically-relevant modulator of ER stress in brown adipocytes and that PTP1B deficiency modulates PERK-eIF2α phosphorylation and protein synthesis.
authors.affiliation: Department of Nutrition, University of California Davis, Davis, California, United States of America.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.forename: Kosuke
authors.initials: K
authors.lastname: Matsuo
authors.forename: Izumi
authors.initials: I
authors.lastname: Matsuo
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.forename: Ramzi
authors.initials: R
authors.lastname: Melhem
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis; D052437:Adipocytes, Brown / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D014443:Tyrosine / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics; D019892:eIF-2 Kinase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051701:Activating Transcription Factor 4; D015852:Eukaryotic Initiation Factor-2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D014443:Tyrosine; D019892:eIF-2 Kinase; C497109:ATF4 protein, human