Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase
Abstract
The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.
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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 [120]
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- Authors
- Kato, S., Endoh, H., Masuhiro, Y., Kitamoto, T., Uchiyama, S., Sasaki, H., Masushige, S., Gotoh, Y., Nishida, E., Kawashima, H., Metzger, D., & Chambon, P.
- Affiliations
- Tokyo University of Agriculture (JP)
- H. Endoh and H. Kawashima, Molecular Medicine Research Laboratory II, Yamanouchi Institute for Drug Discovery Research Co. Ltd., Tsukuba, Ibaraki 305, Japan.
- Kyoto University (JP)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Science
- Published
- 1995-12
- Volume
- 270
- Issue
- 5241
- Pages
- 1491-1494
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2072787342
- Cited by
- 1,964
- References
- 1
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 23 · 2023: 39 · 2022: 31 · 2021: 33 · 2020: 32 · 2019: 43 · 2018: 43 · 2017: 35 · 2016: 37 · 2015: 56 · 2014: 46 · 2013: 67 · 2012: 81
- FWCI
- 38.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- estrogen receptor, mitogen-activated protein kinase, MAPK kinase, Ras, activation functions, transcriptional activation, tamoxifen, epidermal growth factor, insulin-like growth factor, growth factor signaling, receptor activation
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Enzyme Activation, Epidermal Growth Factor, Estradiol, Estrogen Antagonists, Humans, Molecular Sequence Data, Mutation, Phosphorylation, Protein Kinases, Proto-Oncogene Proteins, Receptors, Estrogen, Recombinant Fusion Proteins, Serine, Somatomedins, Tamoxifen, Transfection, Transcriptional Activation, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Proto-Oncogene Proteins c-raf, Mitogen-Activated Protein Kinase Kinases, Polyunsaturated Alkamides
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