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

Date publication

juin 2006

Auteurs

Membres identifiés du Cancéropôle Est :
Dr MORAS Dino , Dr ROCHETTE-EGLY Cécile

Tous les auteurs :
Gaillard E, Bruck N, Brelivet Y, Bour G, Lalevee S, Bauer A, Poch O, Moras D, Rochette-Egly C

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/16769902

Résumé

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.

Référence

Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9548-53