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Activation of SGK1 in endometrial epithelial cells in response to PI3K/AKT inhibition impairs embryo implantation
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Salker, Madhuri S., Steel, Jennifer H., Hosseinzadeh, Zohreh, Nautiyal, Jaya, Webster, Zoe, Singh, Yogesh, Brucker, Sara, Lang, Florian and Brosens, Jan J. (2016) Activation of SGK1 in endometrial epithelial cells in response to PI3K/AKT inhibition impairs embryo implantation. Cellular Physiology and Biochemistry, 39 (5). pp. 2077-2087. doi:10.1159/000447903
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Official URL: http://dx.doi.org/10.1159/000447903
Abstract
Background: Serum & Glucocorticoid Regulated Kinase 1 (SGK1) plays a fundamental role in ion and solute transport processes in epithelia. In the endometrium, down-regulation of SGK1 during the window of receptivity facilitates embryo implantation whereas expression of a constitutively active mutant in the murine uterus blocks implantation. Methods/Results: Here, we report that treatment of endometrial epithelial cells with specific inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT activity pathway results in reciprocal activation of SGK1. Flushing of the uterine lumen of mice with a cell permeable, substrate competitive phosphatidylinositol analogue that inhibits AKT activation (AKT inhibitor III) resulted in Sgk1 phosphorylation, down-regulation of the E3 ubiquitin-protein ligase Nedd4-2, and increased expression of epithelial Na+ channels (ENaC). Furthermore, exposure of the uterine lumen to AKT inhibitor III prior to embryo transfer induced a spectrum of early pregnancy defects, ranging from implantation failure to aberrant spacing of implantation sites. Conclusion: Taken together, our data indicate that the balanced activities of two related serine/threonine kinases, AKT and SGK1, critically govern the implantation process.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Subjects: | Q Science > QP Physiology R Medicine > RG Gynecology and obstetrics |
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| Divisions: | Faculty of Medicine > Warwick Medical School | ||||||
| Library of Congress Subject Headings (LCSH): | Human embryo -- Transplantation, Infertility, Glucocorticoids, Epithelium, Endometrium | ||||||
| Journal or Publication Title: | Cellular Physiology and Biochemistry | ||||||
| Publisher: | Karger | ||||||
| ISSN: | 1015-8987 | ||||||
| Official Date: | 31 October 2016 | ||||||
| Dates: |
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| Date of first compliant deposit: | 17 January 2017 | ||||||
| Volume: | 39 | ||||||
| Number: | 5 | ||||||
| Page Range: | pp. 2077-2087 | ||||||
| DOI: | 10.1159/000447903 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Funder: | Deutsche Forschungsgemeinschaft (DFG), European Molecular Biology Organization (EMBO), Universität Tübingen, University Hospitals Coventry and Warwickshire NHS Trust, Warwick Medical School, Andrew Mellon Foundation (AMF) | ||||||
| Grant number: | ZUK 63 (DFG), ATLF 20-2013 (EMBO), CIG-08-122 (AMF) |
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