Abstract
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 Ser 77. In the presence of retinoic acid ligand (RA), the Ser 77 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 Ser 77>A completely abolishes RARα degradation whereas the mutation Ser 77>E rescues this effect. In addition, we correlate RARα stability to Ser 77 phosphorylation required for the ligand independent transcriptional activity on fgf8 promoter. Finally, we show that the ligand-independent Ser 77 phosphorylation requires the genuine ligand-binding domain.
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