Post-translational modifications of orphan nuclear receptor TR2 - New insights into drug targets for stem cell therapy and the effect of retinoic acid

Testicular receptor 2 (TR2) belongs to the nuclear receptor superfamily that constitutes one of the largest transcription factor families. Due to the lack of specific ligands for TR2 and because TR2 gene knockout mice exhibited no apparent pathological phenotypes in laboratories, it has been a challenge to pursue studies of this mysterious nuclear receptor. Recently, using gene knockdown approaches, we were able to detect its specific biological activity, primarily, in the maintenance of proliferation potential of embryonic stem cells. Further, with proteomic approaches, we have uncovered extensive PTMs of TR2. Specific PTMs of TR2 could differentially regulate its biological activity mediated by multiple signaling pathways including one elicited by the nongenomic action of retinoic acid. These PTMs are involved in TR2 activation, repression, DNA-binding, protein stability, and subcellular distribution. The confirmed PTMs that have a functional consequence on the activity/property of TR2 include phosphorylation, ubiquitination, and SUMOylation. This review summarizes the effects of PTMs, as well as their signaling pathways, on TR2 receptor protein stability, recruitment of coregulators, and subcellular partition, and discusses the potential of developing therapeutics targeting at the regulatory components of stem/precursor cells.