title: PERK utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate Akt activation, and promote adipocyte differentiation.
abstract: The endoplasmic reticulum (ER) resident PKR-like kinase (PERK) is necessary for Akt activation in response to ER stress. We demonstrate that PERK harbors intrinsic lipid kinase, favoring diacylglycerol (DAG) as a substrate and generating phosphatidic acid (PA). This activity of PERK correlates with activation of mTOR and phosphorylation of Akt on Ser473. PERK lipid kinase activity is regulated in a phosphatidylinositol 3-kinase (PI3K) p85α-dependent manner. Moreover, PERK activity is essential during adipocyte differentiation. Because PA and Akt regulate many cellular functions, including cellular survival, proliferation, migratory responses, and metabolic adaptation, our findings suggest that PERK has a more extensive role in insulin signaling, insulin resistance, obesity, and tumorigenesis than previously thought.
authors.affiliation: The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bobrovnikova-Marjon
authors.forename: Dariusz
authors.initials: D
authors.lastname: Pytel
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Riese
authors.forename: Laura Pontano
authors.initials: LP
authors.lastname: Vaites
authors.forename: Nickpreet
authors.initials: N
authors.lastname: Singh
authors.forename: Gary A
authors.initials: GA
authors.lastname: Koretzky
authors.forename: Eric S
authors.initials: ES
authors.lastname: Witze
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000201:enzymology*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D050356:Lipid Metabolism; D051379:Mice; D010712:Phosphatidic Acids / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D010712:Phosphatidic Acids; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase