Non-Genomic Action of Androgens is Mediated by Rapid Phosphorylation and Regulation of Androgen Receptor Trafficking
Open accessAbstract
Background: Testosterone is critical for maintaining spermatogenesis and male fertility. The accomplishment of these processes requires the synergistic actions of the classical and non-classical signaling pathways of androgens. Methods: A murine testicular Sertoli cell line, TM4 cell was used to examine androgen actions in Sertoli cells. Western blot analysis and immunofluorescence assay were employed to study the testosterone-induced Androgen receptor (AR) translocation. Protein phosphorylation antibody array was applied to identify the phosphorylation sites under testosterone treatment, and these findings were verified by Western blot analysis. Results: We found that a physiological dose of testosterone induced fast membrane association of AR. By using a phosphorylation antibody array, several phosphorylation sites, such as MEK1/2 (Ser217/221), Akt (Ser473), and Erk1/2 (Thr202/Tyr204) were rapidly phosphorylated within 5 min of testosterone treatment. Inhibition of the MEK and Akt signaling pathways prevented AR trafficking. Blocking of AR by flutamide eliminated the stimulation effect of testosterone on kinase phosphorylation. Testosterone induced kinase Src phosphorylation, and inhibition of Src restricted AR translocation to the membrane and the nucleus. Conclusion: Findings suggested that the membrane association of AR was mediated by the MEK and Akt phosphorylation signaling pathways, which resulted in Src activation and was initiated by testosterone binding to the membrane-localized AR. This study provides new insights into the testosterone signaling pathway in Sertoli cells, which mediate spermatogenesis. In addition, the study can be used in the diagnosis and treatment of male infertility caused by disorders in spermatogenesis.
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The AR signaling pathway elicits its biological effects through both DNA-binding-dependent and non-DNA-binding-dependent pathways, which may be activated by either cytosolically located AR or membrane-localized AR as well as other membrane-localized receptors.
“The AR signaling pathway elicits its biological effects through both DNA‐binding‐dependent and non‐DNA‐binding‐dependent pathways 32 which may be activated by either cytosolically located AR or membrane localized AR 46 as well as other membrane localized receptors. 35”
From The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments (2022) · cites this paper as [46]
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“In our study we have deliberately focused on the transcriptional activity of AR, its condensate behaviour, cistrome and downstream gene programmes, yet AR also exerts rapid, non-11 genomic actions through various signalling cascades 103–105 , which are not addressed here;”
- Authors
- Deng, Q., Zhang, Z., Wu, Y., Yu, W.-Y., Zhang, J., Jiang, Z.-M., Zhang, Y., Liang, H., & Gui, Y.-T.
- Affiliations
- ShenZhen People’s Hospital (CN)
- Peking University Shenzhen Hospital (CN)
- Venue
- Cellular Physiology and Biochemistry
- Publisher
- S. Karger AG
- Published
- 2017
- Volume
- 43
- Issue
- 1
- Pages
- 223-236
- ISSN
- 1015-8987 (ISSN-L)
- 1421-9778
- OpenAlex
- W2753155361
- Cited by
- 49
- References
- 41
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 8
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- androgen receptor, testosterone, Sertoli cells, receptor phosphorylation, MEK1/2 signaling, Akt signaling, ERK signaling, Src kinase, spermatogenesis, male infertility, flutamide
- MeSH terms
- Animals, Cell Line, Flutamide, Microscopy, Fluorescence, Phosphorylation, Receptors, Androgen, Spermatogenesis, Testosterone, Signal Transduction, src-Family Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Proto-Oncogene Proteins c-akt, Mice, Androgen Receptor Antagonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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