Activation of SGK1 in endometrial epithelial cells in response to PI3K/AKT inhibition impairs embryo implantation

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Title: Activation of SGK1 in endometrial epithelial cells in response to PI3K/AKT inhibition impairs embryo implantation
Author(s): Salker, MS
Steel, JH
Hosseinzadeh, Z
Nautiyal, J
Webster, Z
Singh, Y
Brucker, S
Lang, F
Brosens, JJ
Item Type: Journal Article
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.
Publication Date: 31-Oct-2016
Date of Acceptance: 1-Sep-2016
URI: http://hdl.handle.net/10044/1/43896
DOI: http://dx.doi.org/10.1159/000447903
ISSN: 1421-9778
Publisher: Karger Publishers Open Access
Start Page: 2077
End Page: 2087
Journal / Book Title: Cellular Physiology and Biochemistry
Volume: 39
Issue: 5
Copyright Statement: © 2016 The Authors. Published by Karger Publishers Open Access. This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Physiology
Serum/Glucocorticoid Regulated Kinase 1
Epithelial Na+ channel (ENaC)
Nedd4-2
Implantation failure
INDUCIBLE KINASE SGK1
CHANNEL ENAC
SERUM
EXPRESSION
FAILURE
RECEPTIVITY
PREGNANCY
Physiology
1116 Medical Physiology
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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