Serine 157, a retinoic acid receptor α residue phosphorylated by protein kinase C in vitro, is involved in RXR•RARα heterodimerization and transcriptional activity

Retinoic acid (RA) regulation of cellular proliferation and differentiation is mediated, at least in part, through two related nuclear receptors, RAR and RXR. RA-induced modulation of gene expression leads generally to cellular differentiation, whereas stimulation of the protein kinase C (PHC) signaling pathway is associated with cellular proliferation. Pursuant to our discovery that prolonged activation of PKCs induced a strong decrease in RA responsiveness of a retinoid-inducible reporter gene, we have further investigated the connections between these two signaling pathways. We demonstrate that PKC isoforms alpha and gamma are able to phosphorylate human RAR alpha (hRAR alpha) in vitro on a single serine residue located in the extended DNA binding domain (T box). The introduction of a negative charge at this position (serine 157) strongly decreased hRAR alpha transcriptional activity, whereas a similar mutation at other PKC consensus phosphorylation sites had no effect. The effect on transcriptional activation was correlated with a decrease in the capacity of hRAR alpha to heterodimerize with hRXR alpha. Thus hRAR alpha is a direct target for PKC alpha and gamma, which may control retinoid receptor transcriptional activities during cellular proliferation and differentiation.