P38MAPK-dependent phosphorylation and degradation of SRC-3/AIB1 and RARα-mediated transcription

Nuclear retinoic acid ( RA) receptors ( RARs) activate gene expression through dynamic interactions with coregulators in coordination with the ligand and phosphorylation processes. Here we show that during RA- dependent activation of the RAR alpha isotype, the p160 coactivator pCIP/ ACTR/ AIB- 1/ RAC- 3/ TRAM- 1/ SRC- 3 is phosphorylated by p38MAPK. SRC- 3 phosphorylation has been correlated to an initial facilitation of RAR alpha- target genes activation, via the control of the dynamics of the interactions of the coactivator with RARa. Then, phosphorylation inhibits transcription via promoting the degradation of SRC- 3. In line with this, inhibition of p38MAPK markedly enhances RARa- mediated transcription and RA- dependent induction of cell differentiation. SRC- 3 phosphorylation and degradation occur only within the context of RARa complexes, suggesting that the RAR isotype defines a phosphorylation code through dictating the accessibility of the coactivator to p38MAPK. We propose a model in which RARa transcriptional activity is regulated by SRC- 3 through coordinated events that are fine- tuned by RA and p38MAPK.