Minireview: Tipping the balance: ligand-independent activation of steroid receptors.

Steroid receptors are prototypical ligand-dependent transcription factors and a textbook example for allosteric regulation. According to this canonical model, binding of cognate steroid is an absolute requirement for transcriptional activation. Remarkably, the simple one ligand-one receptor model could not be farther from the truth. Steroid receptors, notably the sex steroid receptors, can receive multiple inputs. Activation of steroid receptors by other signals, working through their own signaling pathways, in the absence of the cognate steroids, represents the most extreme form of signaling cross talk. Compared with cognate steroids, ligand-independent activation pathways produce similar but not identical outputs. Here we review the phenomena and discuss what is known about the underlying molecular mechanisms and the biological significance. We hypothesize that steroid receptors may have evolved to be trigger happy. In addition to their cognate steroids, many posttranslational modifications and interactors, modulated by other signals, may be able to tip the balance.