ArticleMolecular endocrinology (Baltimore, Md.)2012
ERα phosphorylation at Y537 by Src triggers E6-AP-ERα binding, ERα ubiquitylation, promoter occupancy, and target gene expression.
Article in Molecular endocrinology (Baltimore, Md.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
47 citing papers in PubMed, 76 citations in OpenAlex.
- LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.The Journal of clinical investigation · 2014Trial
- Nucleic sexual hormone receptor signaling pathways in breast cancer: function regulation, crosstalk, and therapeutic implications.NPJ precision oncology · 2026Review
- Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism.eLife · 2025Article
- Context-Dependent Estrogenic Actions of (+)-Pisatin Produced in Elicited Green or Snow Pea (Journal of agricultural and food chemistry · 2024Article
- TRIM33 Is a Co-Regulator of Estrogen Receptor Alpha.Cancers · 2024Article
- Stabilization of estrogen receptor α by USP37 contributes to the progression of breast cancer.Cancer science · 2023Article
- Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression.The Journal of clinical investigation · 2023Article
- ERK1/2-RSK regulation of oestrogen homeostasis.The FEBS journal · 2023Review
- Estrogen signaling via estrogen receptor alpha and its implications for neurodegeneration associated with Alzheimer's disease in aging women.Metabolic brain disease · 2023Review
- AKTIP loss is enriched in ERα-positive breast cancer for tumorigenesis and confers endocrine resistance.Cell reports · 2022Article
- Article
- FKBP52 and FKBP51 differentially regulate the stability of estrogen receptor in breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer.Frontiers in endocrinology · 2022Review
- Five-year survival in luminal breast cancer patients: relation with intratumoral activity of proteasomes.Translational breast cancer research : a journal focusing on translational research in breast cancer · 2022Article
- Calcineurin regulates the stability and activity of estrogen receptor α.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- MINDY1 promotes breast cancer cell proliferation by stabilizing estrogen receptor α.Cell death & disease · 2021Article
- OTUD7B stabilizes estrogen receptor α and promotes breast cancer cell proliferation.Cell death & disease · 2021Article
- Review
- TRIM11 promotes breast cancer cell proliferation by stabilizing estrogen receptor α.Neoplasia (New York, N.Y.) · 2020Article
- Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation.Biomolecules · 2020Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Many transcription factors undergo transcription-coupled proteolysis. Although ligand binding activates ubiquitin proteolysis of estrogen receptor α (ERα), mechanisms governing this and its relationship to transcriptional activation were unclear. Data presented link cross talk between the Src kinase and liganded ERα with ERα activation and its ubiquitylation. Liganded ERα rapidly activates and recruits Src, which phosphorylates ERα at tyrosine 537 (Y537). This enhances ERα binding to the ubiquitin ligase/ERα coactivator, E6-associated protein (E6-AP), stimulating ERα ubiquitylation, target gene activation, and ultimately ERα loss. ERα phosphorylation by Src promotes ERα ubiquitylation by E6-AP and proteasomal degradation in vitro. Src inhibition impairs estrogen (E2)-activated ERα:E6-AP binding, reducing ERα degradation. ERα-Y537F shows little E2-stimulated degradation and activates native ERα target genes poorly. Src activation enhances ERα and E6-AP binding and their occupancy at ERα target gene promoters to enhance transcription. Thus, ERαY537 phosphorylation drives ERα:E6-AP binding to at least a subset of target promoters, linking transcriptional activation to ERα degradation and providing a novel mechanism to fine tune ERα action. The observation that ERα transcriptional activity can be briskly maintained in a context of reduced ERα levels raises the possibility that hormonally sensitive tissues may not always show robust ERα protein levels.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.