title: Oestrogen receptors interact with the α-catalytic subunit of AMP-activated protein kinase.
abstract: Normal and pathological stressors engage the AMP-activated protein kinase (AMPK) signalling axis to protect the cell from energetic pressures. Sex steroid hormones also play a critical role in energy metabolism and significantly modify pathological progression of cardiac disease, diabetes/obesity and cancer. AMPK is targeted by 17β-oestradiol (E2), the main circulating oestrogen, but the mechanism by which E2 activates AMPK is currently unknown. Using an oestrogen receptor α/β (ERα/β) positive (T47D) breast cancer cell line, we validated E2-dependent activation of AMPK that was mediated through ERα (not ERβ) by using three experimental strategies. A series of co-immunoprecipitation experiments showed that both ERs associated with AMPK in cancer and striated (skeletal and cardiac) muscle cells. We further demonstrated direct binding of ERs to the α-catalytic subunit of AMPK within the βγ-subunit-binding domain. Finally, both ERs interacted with the upstream liver kinase B 1 (LKB1) kinase complex, which is required for E2-dependent activation of AMPK. We conclude that E2 activates AMPK through ERα by direct interaction with the βγ-binding domain of AMPKα.
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85724, U.S.A. Department of Physiology, University of Arizona, Tucson, AZ 85724, U.S.A.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Lipovka
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ 85724, U.S.A. Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85724, U.S.A.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: The BIO5 Research Institute, University of Arizona, Tucson, AZ 85724, U.S.A.
authors.forename: Josef
authors.initials: J
authors.lastname: Vagner
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85724, U.S.A.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.affiliation: Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, AZ 85724, U.S.A.
authors.forename: Tsu-Shuen
authors.initials: TS
authors.lastname: Tsao
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ 85724, U.S.A. Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85724, U.S.A. konhilas@arizona.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Konhilas
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D001940:Breast / Q000201:enzymology / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D020134:Catalytic Domain; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D006801:Humans
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004958:Estradiol; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase (AMPK); breast cancer; oestradiol; oestrogen receptors