Extra-nuclear signaling of estrogen receptors

Estrogen controls multiple biological functions through binding to estrogen receptors (ERs). Traditionally, ERs have been regarded as transcription factors regulating the expression of target genes. However, growing evidence of rapid estrogen's actions in a number of tissues has been accumulating and alternative mechanisms of signal transduction have been proposed. These so called "extra-nuclear actions" do not require gene expression or protein synthesis and are independent of the nuclear localization of ERs. Indeed, some of these actions are elicited by ERs residing at or near the plasma membrane. Membrane-associated molecules such as ion channels, G proteins, the tyrosine kinase c-Src as well as growth factor receptors are modulated by liganded ERs within the membrane, leading to the activation of downstream cascades such as mitogen-activated protein kinase, phosphatidylinositol 3-OH kinase, protein kinase A, and protein kinase C. These cascades mediate some important rapid actions of estrogen, such as the activation of nitric oxide synthesis or the remodeling of actin cytoskeleton. In addition, these pathways are critical for the regulation of the expression of a number of target proteins implicated in cell proliferation, apoptosis, differentiation, movement, and homeostasis. In this manner, the extra-nuclear pathways are tightly integrated with the genomic pathways to orchestrate the full spectrum of estrogen's biological functions. The recent advancements in the characterization of the molecular basis of the extra-nuclear signaling of estrogen helps to understand the role of estrogen on human cells, and may in future turn out to be of relevance for clinical purposes.