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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 ISSN 1015-8987.

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Official URL: http://dx.doi.org/10.1159/000447903

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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
Divisions: Faculty of Science, Engineering and Medicine > 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:
DateEvent
31 October 2016Available
1 September 2016Accepted
Volume: 39
Number: 5
Page Range: pp. 2077-2087
DOI: 10.1159/000447903
Status: Peer Reviewed
Publication Status: Published
Date of first compliant deposit: 17 January 2017
Date of first compliant Open Access: 17 January 2017
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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