The peptidyl-prolyl isomerase Pin1 regulates phospho-Ser77 retinoic acid receptor alpha 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 (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.
Brondani
Vincent
V
Institute of Medical Microbiology, University of Basel, Peterplatz 10, CH-4003, Basel, Switzerland. vincent.brodani@unibas.ch
Schefer
Quirino
Q
Hamy
François
F
Klimkait
Thomas
T
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D004795:Enzyme Stability; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000097768:Retinoic Acid Receptor gamma
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D000072482:Retinoic Acid Receptor alpha; D012694:Serine; D000097768:Retinoic Acid Receptor gamma