The peptidyl-prolyl isomerase Pin1 regulates phospho-Ser77 retinoic acid receptor α stability

Peptidyl-prolyl isomerases (PPIase) facilitate the cis-trans interconversion of the peptidyl-prolyl bond and in such way affect protein folding. Pin1 is a PPIase, which specifically recognizes phosphorylated S/T-P bonds. The transcription factor TFIIH mediates phosphorylation of the retinoic acid receptor alpha (RARα) at position Ser77. In the presence of retinoic acid ligand (RA), the Ser77 non-phosphorylated receptor is suggested to undergo degradation through the proteasome pathway. Here we provide evidence that Pin1 is able to selectively destabilize RARα in a ligand independent-manner. We show that this is caused by RARα ubiquitination, which in turn is phosphorylation dependent. The single mutation Ser77>A completely abolishes RARα degradation whereas the mutation Ser77>E rescues this effect. In addition, we correlate RARα stability to Ser77 phosphorylation required for the ligand independent transcriptional activity on fgf8 promoter. Finally, we show that the ligand-independent Ser77 phosphorylation requires the genuine ligand-binding domain.