Understanding extranuclear (nongenomic) androgen signaling: What a frog oocyte can tell us about human biology

Steroids are key factors in a myriad of mammalian biological systems, including the brain, kidney, heart, bones, and gonads. While alternative potential steroid receptors have been described, the majority of biologically relevant steroid responses appear to be mediated by classical steroid receptors that are located in all parts of the cell, from the plasma membrane to the nucleus. Interestingly, these classical steroid receptors modulate different signals depending upon their location. For example, receptors in the plasma membrane interact with membrane signaling molecules, including G proteins and kinases. In contrast, receptors in the nucleus interact with nuclear signaling molecules, including transcriptional co-regulators. These extranuclear and intranuclear signals function together in an integrated fashion to regulate important biological functions. While most studies on extranuclear steroid signaling have focused on estrogens, recent work has demonstrated that nongenomic androgen signaling is equally important and that these two steroids modulate similar signaling pathways. In fact, by taking advantage of a simple model system whereby a physiologically relevant androgen-mediated process is regulated completely independent of transcription (Xenopus laevis oocyte maturation), many novel and conserved concepts in nongenomic steroid signaling have been uncovered and characterized.

► Nongenomic androgen signaling is conserved from lower to higher vertebrates. ► Extranuclear androgens signal via classical androgen receptors. ► Extranuclear androgen signaling modules cytoplasmic kinases. ► Extranuclear androgen signaling modulates intranuclear transcription. ► Paxillin mediates crosstalk between cytoplasmic and nuclear signaling.