title: Phosphorylation by PKA potentiates retinoic acid receptor alpha activity by means of increasing interaction with and phosphorylation by cyclin H/cdk7.
abstract: Nuclear retinoic acid receptors (RARs) work as ligand-dependent heterodimeric RAR/retinoid X receptor transcription activators, which are targets for phosphorylations. The N-terminal activation function (AF)-1 domain of RARalpha is phosphorylated by the cyclin-dependent kinase (cdk) 7/cyclin H complex of the general transcription factor TFIIH and the C-terminal AF-2 domain by the cAMP-dependent protein kinase A (PKA). Here, we report the identification of a molecular pathway by which phosphorylation by PKA propagates cAMP signaling from the AF-2 domain to the AF-1 domain. The first step is the phosphorylation of S369, located in loop 9-10 of the AF-2 domain. This signal is transferred to the cyclin H binding domain (at the N terminus of helix 9 and loop 8-9), resulting in enhanced cyclin H interaction and, thereby, greater amounts of RARalpha phosphorylated at S77 located in the AF-1 domain by the cdk7/cyclin H complex. This molecular mechanism relies on the integrity of the ligand-binding domain and the cyclin H binding surface. Finally, it results in higher DNA-binding efficiency, providing an explanation for how cAMP synergizes with retinoic acid for transcription.
authors.affiliation: Département de Biologie Cellulaire et de Transduction du Signal, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM, Université Louis Pasteur, Unité Mixte de Recherche 7104, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Gaillard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bruck
authors.forename: Yann
authors.initials: Y
authors.lastname: Brelivet
authors.forename: Gaétan
authors.initials: G
authors.lastname: Bour
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lalevée
authors.forename: Annie
authors.initials: A
authors.lastname: Bauer
authors.forename: Olivier
authors.initials: O
authors.lastname: Poch
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Cécile
authors.initials: C
authors.lastname: Rochette-Egly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D056748:Cyclin H; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction
chemical_list: C534751:CCNH protein, human; D056748:Cyclin H; D016213:Cyclins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D010768:Phosphoserine; D004247:DNA; D017868:Cyclic AMP-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases