EXTRA-NUCLEAR ESTROGEN RECEPTOR SIGNALING

Abstract

Steroid hormones produce rapid effects that result from engaging specific receptors localized most often to the plasma membrane. Membrane-initiated steroid signaling (MISS)1 includes rapid signal transduction that leads to the modification of existing proteins and cell behaviors. Rapid signaling through calcium, amine release, and kinase activation also impacts the regulation of gene expression by steroids, sometimes requiring integration with nuclear steroid receptor function. In this and other ways way, the integration of all steroid actions in the cell co-ordinates outcomes such as cell fate, proliferation, differentiation, and migration. The nature of the receptors is of intense interest and recent data suggests that extra-nuclear and nuclear steroid receptor pools are the same proteins. Recent insights as to the structural determinants for membrane localization and function, and interactions with G proteins and other signal molecules in confined areas of the membrane lead to a fuller understanding of how steroid receptors such as the estrogen receptor (ER) effect rapid actions. Increasingly, the relevance of rapid signaling for the in-vivo functions of ER has been established. This impacts reproductive organ development and function, cardiovascular and bone biology, and steroid-responsive cancer biology. Receptors in other cell sites including mitochondria support important effects of estrogen that are relevant to breast cancer. Overall, there must be integration of the signals generated at each localized ER pool to produce a net steroid action.