Insights from post-translational modifications of orphan nuclear receptors TR2 and TR4

Nuclear receptors (NRs) constitute one of the largest families of transcription factors that play important physiological roles. Among the 48 NRs identified in the human genome, approximately half are orphan members whose ligands remain to be identified. Testicular receptor-2 (TR2) and -4 (TR4) belong to the orphan category and represent a more ancestral subfamily. Classical molecular studies demonstrate their biological activities in regulating several hormone responsive genes; however, the molecular detail of their biological activity remained unresolved until recently. Gene knockdown studies suggest multiple physiological functions for TR4, and studies of stem cells reveal the physiological function of TR2 specifically in cell proliferation. More recent proteomic endeavor has uncovered extensive protein post-translational modification (PTM) of TR2 and TR4 and begun to elucidate the molecular basis underlying their ligand-independent biological activities in gene regulation. TR2 and TR4 can be modified by phosphorylation, sumoylation and lysine methylation, and each form of PTM modulates their biological activities in a distinct manner. Studies of PTM have considerably facilitated the verification of the biological activities of TR2 and TR4. With data gathered from recent studies of PTM, the biological relevance of this once disregarded family of transcription factors has been redefined.