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

Abstract

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 (PKC) 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 α and γ are able to phosphorylate human RARα (hRARα) 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 hRARα 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 hRARα to heterodimerize with hRXRα. Thus hRARα is a direct target for PKCα and γ, which may control retinoid receptor transcriptional activities during cellular proliferation and differentiation.