Integration of the extranuclear and nuclear actions of estrogen
Open accessAbstract
Estrogen receptors (ERs) are localized to many sites within the cell, potentially contributing to overall estrogen action. In the nucleus, estrogen mainly modulates gene transcription, and the resulting protein products determine the cell biological actions of the sex steroid. In addition, a small pool of ERs localize to the plasma membrane and signal mainly though coupling, directly or indirectly, to G proteins. In response to steroid, signal transduction modulates both nontranscriptional and transcriptional events and impacts both the rapid and more prolonged actions of estrogen. Cross-talk from membrane-localized ERs to nuclear ERs can be mediated through growth factor receptor tyrosine kinases, such as epidermal growth factor receptor and IGF-I receptor. Growth factor receptors enact signal transduction to kinases such as ERK and phosphatidylinositol 3-kinase that phosphorylate and activate nuclear ERs, and this can also occur in the absence of sex steroid. A complex relationship between the membrane and nuclear effects of estrogen also involves membrane-initiated phosphorylation of coactivators, recruiting these proteins to the nuclear transcriptosome. Finally, large pools of cytoplasmic ERs exist, and some are localized to mitochondria. The integration of sex steroid effects at distinct cellular locations of its receptor leads to important cellular physiological outcomes and are manifest in both reproductive and nonreproductive organs.
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Estrogens can exert receptor-mediated non-genomic effects via GPER1, including interactions with caveolin-1, other G-proteins, and receptor tyrosine kinases such as EGFR, IGF-1, and MAPK.
“Estrogens can also exert receptor-mediated non-genomic effects via GPER1, including interactions with cell membrane-associated complexes such as caveolin-1, other G-proteins, and receptor tyrosine kinases such as EGFR, IGF-1, and MAPK (119, 120).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [119]
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- Authors
- Levin, E. R.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Levin, Ellis R.
- ORCID
- Levin, Ellis R.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2005-08-01
- Volume
- 19
- Issue
- 8
- Pages
- 1951-1959
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2148788638
- Cited by
- 708
- References
- 2
- Citations by year
- 2026: 14 · 2025: 7 · 2024: 9 · 2023: 19 · 2022: 20 · 2021: 22 · 2020: 21 · 2019: 14 · 2018: 25 · 2017: 38 · 2016: 28 · 2015: 30 · 2014: 35 · 2013: 27 · 2012: 51
- FWCI
- 6.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- National Cancer Institute (R01CA100366, CA 100366)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- estrogen receptor, membrane estrogen receptor, nuclear estrogen receptor, estrogen signaling, G protein-coupled receptor signaling, receptor tyrosine kinase, epidermal growth factor receptor, IGF-1 receptor, ERK, phosphatidylinositol 3-kinase, cytoplasmic estrogen receptor, gene transcription
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