Phosphorylation by PKA potentiates retinoic acid receptor alpha activity by means of increasing interaction with and phosphorylation by cyclin H/cdk7.

Emilie Gaillard , Nathalie Bruck (1) , Yann Brelivet , Gaétan Bour (1) , Sébastien Lalevée , Annie Bauer (1) , Olivier Poch (1) , Dino Moras (1) , Cécile Rochette-Egly (1)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

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.

Domaines: Biologie moléculaire

Emilie Gaillard, Nathalie Bruck, Yann Brelivet, Gaétan Bour, Sébastien Lalevée, et al.. Phosphorylation by PKA potentiates retinoic acid receptor alpha activity by means of increasing interaction with and phosphorylation by cyclin H/cdk7.. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103 (25), pp.9548-53. ⟨10.1073/pnas.0509717103⟩. ⟨hal-00187915⟩