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

Biochem Biophys Res Commun. 2005 Mar 4;328(1):6-13. doi: 10.1016/j.bbrc.2004.12.130.


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 (RARalpha) 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 RARalpha in a ligand independent-manner. We show that this is caused by RARalpha ubiquitination, which in turn is phosphorylation dependent. The single mutation Ser77>A completely abolishes RARalpha degradation whereas the mutation Ser77>E rescues this effect. In addition, we correlate RARalpha 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.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Enzyme Activation
  • Enzyme Stability
  • Gene Expression Regulation, Enzymologic / physiology*
  • Homeostasis / physiology
  • Mutagenesis, Site-Directed
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphorylation
  • Protein Binding
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Recombinant Proteins / metabolism
  • Retinoic Acid Receptor alpha
  • Retinoic Acid Receptor gamma
  • Serine / genetics
  • Serine / metabolism*
  • Structure-Activity Relationship


  • NIMA-Interacting Peptidylprolyl Isomerase
  • Receptors, Retinoic Acid
  • Recombinant Proteins
  • Retinoic Acid Receptor alpha
  • Serine
  • Peptidylprolyl Isomerase