Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes

Abstract

Remarkable progress in recent years has suggested that estrogen action in vivo is complex and often involves activation of cytoplasmic signaling cascades in addition to genomic actions mediated directly through estrogen receptors α and β. Rather than a linear response mediated solely through estrogen-responsive DNA elements, in vivo estrogen might simultaneously activate distinct signaling cascades that function as networks to coordinate tissue responses to estrogen. This complex signaling system provides for exquisite control and plasticity of response to estrogen at the tissue level, and undoubtedly contributes to the remarkable tissue-specific responses to estrogens. In part I of this series, we summarize cytoplasmic signaling modules involving estrogen or estrogen receptors, with particular focus on recently described membrane-associated signaling complexes.Knowledge of the molecular mechanism of estrogen action has evolved rapidly during the past two decades. It is now accepted that two proteins serve as receptors for 17β estradiol (E 2 ), estrogen receptors α and β (ERα, ERβ). These receptors function as ligand-dependent transcription factors to increase gene transcription from promoters by direct binding of the receptor to specific DNA target sequences, designated estrogen response elements (EREs). Association of receptors with the gene transcription machinery involves essential coregulatory proteins that contribute to estrogen action and that can enhance or repress ER action (see Refs [1][2][3]). The importance of this signaling pathway in vivo has been substantiated using several approaches, including targeted gene disruption (knockout) in mice [4][5][6][7][8]. Within the ER proteins, there are two activating functions corresponding to the N-terminus (AF-1) or ligand-binding region (AF-2) of the molecule [9] (and Refs therein). In addition, ER function is modified by its phosphorylation [10,11]. The genomic actions of E 2 proceeding through augmentation or repression of ERE-containing promoters by ERs α and β have been designated the classic pathway of estrogen action [12]. In addition, ER acts through AP-1 and SP-1 to affect transcription.* segarsj@mail.nih.gov. In spite of the clarity with which the ER has been shown to act as a transcription factor, it has been apparent for several years that not all physiological effects of E 2 are accomplished through a direct effect on gene transcription [13]. Definition of the classic estrogen-signaling pathway highlighted the fact that, in many instances, another signaling pathway(s) involving cytoplasmic proteins, growth factors and/or membrane-initiated responses contributed to estrogen action (reviewed in Refs [14][15][16][17][18]). In Part I of this review, we focus on membraneassociated estrogen action, particularly cellular responses observed within minutes of estrogen exposure. Part II (to be published in the December issue of TEM) covers cytoplasmic cascades initiated by growth factors, and involvement of the ER in second messenger signaling casc...

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

“…34,35 Estrogen binds on both ER-α and ER-β receptors; however, binding results in partially overlapping but also differential transcriptional effects. 36,37 Alternative action mechanisms involve interactions with other transcription factors, ligand-independent receptor activation, and activation of different signaling pathways. For instance, it has been shown that ER-β can activate specific MAPK pathways in human colon cancer cell lines.…”

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

“…Statistical differences between the stimulated and vehicle-treated samples were determined by student's ttest. *P < 0.05, **P < 0.01, ***P < 0.005. based estrogen signaling results in activation of the MAPK and Akt pathways (Razandi et al, 2002;Segars and Driggers, 2002).…”

“…Moreover, it has been known for several years that the physiological function of estrogens involves not only a direct effect on gene transcription, but also activation of rapid cytoplasmic signaling mediated by a membraneassociated estrogen receptor (mER) in many cells (Acconcia and Kumar, 2006;Segars and Driggers, 2002). The mER is physically associated with caveolin-1, and a variety of proximal signaling molecules, including G-proteins (Razandi et al, 2002).…”

Functional significance of the rapid regulation of brain estrogen action: Where do the estrogens come from?

“…The existence of membrane estrogen receptors was first proposed in 1977 by Pietras and Szego [195]. Since then, an important controversy developed concerning the nature of this (these) receptor(s) (for review see [45,143,177,232,259,273]). In brief, one hypothesis postulates the existence of novel membrane receptors, such as GPR30 [89] and ER-X [260], that are different from the classical nuclear receptors, while the alternative hypothesis supports the involvement of the classical nuclear receptors, ERα and ERβ, that would be able to integrate the cell membrane and activate various intracellular cascades.…”