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.
© 2016 The Author(s) Published by S. Karger AG, Basel.
MeSH terms
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Animals
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Cell Line
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Embryo Implantation / drug effects*
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Endometrium / cytology
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Endometrium / drug effects
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Endometrium / metabolism
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Endosomal Sorting Complexes Required for Transport / genetics
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Endosomal Sorting Complexes Required for Transport / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Sodium Channels / genetics
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Epithelial Sodium Channels / metabolism
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Female
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Gene Expression Regulation
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Humans
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Immediate-Early Proteins / agonists
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Immediate-Early Proteins / genetics*
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Immediate-Early Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Nedd4 Ubiquitin Protein Ligases
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositols / pharmacology*
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Phosphoinositide-3 Kinase Inhibitors
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Pregnancy
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Endosomal Sorting Complexes Required for Transport
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Epithelial Sodium Channels
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Immediate-Early Proteins
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Phosphatidylinositols
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Nedd4 Ubiquitin Protein Ligases
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Nedd4 protein, human
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Nedd4L protein, human
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Nedd4l protein, mouse
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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serum-glucocorticoid regulated kinase