title: The nuclear protein Artemis promotes AMPK activation by stabilizing the LKB1-AMPK complex.
abstract: AMP-activated protein kinase (AMPK) is a hetero-trimeric Ser/Thr kinase composed of a catalytic α subunit and regulatory β and γ subunits; it functions as an energy sensor that controls cellular energy homeostasis. In response to an increased cellular AMP/ATP ratio, AMPK is activated by phosphorylation at Thr172 in the α-subunit by upstream AMPK kinases (AMPKKs), including tumor suppressor liver kinase B1 (LKB1). To elucidate more precise molecular mechanisms of AMPK activation, we performed yeast two-hybrid screening and isolated the complementary DNA (cDNA) encoding the nuclear protein Artemis/DNA cross-link repair 1C (DCLRE1C) as an AMPKα2-binding protein. Artemis was found to co-immunoprecipitate with AMPKα2, and the co-localization of Artemis with AMPKα2 in the nucleus was confirmed by immunofluorescence staining in U2OS cells. Moreover, over-expression of Artemis enhanced the phosphorylation of AMPKα2 and the AMPK substrate acetyl-CoA carboxylase (ACC). Conversely, RNAi-mediated knockdown of Artemis reduced AMPK and ACC phosphorylation. In addition, Artemis markedly increased the physical association between AMPKα2 and LKB1. Taken together, these results suggest that Artemis functions as a positive regulator of AMPK signaling by stabilizing the LKB1-AMPK complex.
authors.affiliation: Department of Pathophysiology and Therapeutics, Division of Pharmascience, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan. k_nakagawa@pharm.hokudai.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Uehata
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Natsuizaka
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kohara
authors.forename: Stephanie
authors.initials: S
authors.lastname: Darmanin
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004720:Endonucleases; D004795:Enzyme Stability; D006801:Humans; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C426344:DCLRE1C protein, human; D004720:Endonucleases