Cross‐Talk between PPARs and the Partners of RXR: A Molecular Perspective

The PPARs are integral parts of the RXR‐dependent signaling networks. Many other nuclear receptor subfamily 1 members also require RXR as their obligatory heterodimerization partner and they are often co‐expressed in any given tissue. Therefore, the PPARs often complete with other RXR‐dependent nuclear receptors and this competition has important biological implications. Thorough understanding of this cross‐talk at the molecular level is crucial to determine the detailed functional roles of the PPARs. At the level of DNA binding, most RXR heterodimers bind selectively to the well‐known “DR1 to 5” DNA response elements. As a result, many heterodimers share the same DR element and must complete with each other for DNA binding. At the level of heterodimerization, the partners of RXR share the same RXR dimerization interface. As a result, individual nuclear receptors must complete with each other for RXR to form functional heterodimers. Cross‐talk through DNA binding and RXR heterodimerization present challenges to the study of these nuclear receptors that cannot be adequately addressed by current experimental approaches. Novel tools, such as engineered nuclear receptors with altered dimerization properties, are currently being developed. These tools will enable future studies to dissect specific RXR heterodimers and their signaling pathways.