Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 39, Issue 5, Pages 2077-2087Publisher
KARGER
DOI: 10.1159/000447903
Keywords
Serum/Glucocorticoid Regulated Kinase 1; Epithelial Na+ channel (ENaC); Nedd4-2; Implantation failure
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Funding
- Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of Tuebingen University
- EMBO Long Term Postdoctoral fellowship [ATLF 20-2013]
- Institutional Strategy of the University of Tubingen (Deutsche Forschungsgemeinschaft) [ZUK 63]
- Biomedical Research Unit in Reproductive Health
- Contraceptive Research and Development Program Consortium for Industrial Collaboration in Contraceptive Research [CIG-08-122]
- University Hospitals Coventry and Warwickshire NHS Trust
- Warwick Medical School
- University Hospitals Coventry
- Warwickshire NHS Trust and Warwick Medical School
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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. (C) 2016 The Author(s) Published by S. Karger AG, Basel
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