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Phosphorylation of a Conserved Serine in the Deoxyribonucleic Acid Binding Domain of Nuclear Receptors Alters Intracellular Localization

Environmental Toxicology Graduate Program (K.S.), Department of Cell Biology and Neuroscience (V.M., V.P., F.M.S.), Cell, Molecular and Developmental Biology Graduate Program (K.C.), University of California, Riverside, California 92521; Center for Cell Signaling (B.M.P.), Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908; Département de Biologie et Génomique Structurales (Y.B., D.M.), Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; and Division of Pulmonary Biology (Y.M.), Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229

Address all correspondence and requests for reprints to: Dr. Frances M. Sladek, Department of Cell Biology and Neuroscience, 2115 Biological Sciences Building, University of California, Riverside, California 92521-0314. E-mail: frances.sladek{at}ucr.edu.

Nuclear receptors (NRs) are a superfamily of transcription factors whose genomic functions are known to be activated by lipophilic ligands, but little is known about how to deactivate them or how to turn on their nongenomic functions. One obvious mechanism is to alter the nuclear localization of the receptors. Here, we show that protein kinase C (PKC) phosphorylates a highly conserved serine (Ser) between the two zinc fingers of the DNA binding domain of orphan receptor hepatocyte nuclear factor 4 (HNF4). This Ser (S78) is adjacent to several positively charged residues (Arg or Lys), which we show here are involved in nuclear localization of HNF4 and are conserved in nearly all other NRs, along with the Ser/threonine (Thr). A phosphomimetic mutant of HNF4 (S78D) reduced DNA binding, transactivation ability, and protein stability. It also impaired nuclear localization, an effect that was greatly enhanced in the MODY1 mutant Q268X. Treatment of the hepatocellular carcinoma cell line HepG2 with PKC activator phorbol 12-myristate 13-acetate also resulted in increased cytoplasmic localization of HNF4 as well as decreased endogenous HNF4 protein levels in a proteasome-dependent fashion. We also show that PKC phosphorylates the DNA binding domain of other NRs (retinoic acid receptor , retinoid X receptor , and thyroid hormone receptor ß) and that phosphomimetic mutants of the same Ser/Thr result in cytoplasmic localization of retinoid X receptor and peroxisome proliferator-activated receptor . Thus, phosphorylation of this conserved Ser between the two zinc fingers may be a common mechanism for regulating the function of NRs.

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Nuclear Receptors:   TRβ  |  RARα  |  PPARα  |  VDR  |  PXR  |  HNF4α  |  RXRα  |  ERα  |  GR  |  MR  |  PR  |  AR

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