A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

• Published in: The Journal of biological chemistry 2009-07, Vol.284 (27), p.18503
• Main Authors: Young-Hoon Han, Hu Zhou, Jin-Hee Kim, Ting-dong Yan, Kee-Ho Lee, Hua Wu, Feng Lin, Na Lu, Jie Liu, Jin-zhang Zeng, Xiao-kun Zhang
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.007708

Recent evidence suggests that extranuclear action of retinoid receptors is involved in mediating the pleiotropic effects of retinoids. However, whether they reside in the cytoplasm remains elusive. Here, we showed that retinoic acid receptor-γ (RARγ) was cytoplasmic in confluent cells, or when cells were released from serum depletion or treated with growth factors. In studying the regulation of RARγ subcellular localization, we observed that ectopically overexpressed RARγ was mainly cytoplasmic irrespective of serum concentration and cell density. The cytoplasmic retention of RARγ was inhibited by ligand retinoic acid (RA). In addition, coexpression of retinoid X receptor-α (RXRα) resulted in nuclear localization of RARγ through their heterodimerization. Mutagenesis studies revealed that a C-terminal fragment of RXRα potently prevents RA-induced RARγ nuclear localization and transcriptional function. Furthermore, our results showed that the cytoplasmic retention of RARγ was due to the presence of its unique N-terminal A/B domain, which was subject to regulation by p38 MAPK-mediated phosphorylation. Deletion or mutation of the N-terminal A/B domain largely impaired its cytoplasmic localization. Together, our data demonstrate that the subcellular localization of RARγ is regulated by complex interactions among ligand binding, receptor phosphorylation, and receptor dimerizations.