WNK1 regulates uterine homeostasis and its ability to support pregnancy
WNK1 (with no lysine [K] kinase 1) is an atypical kinase protein ubiquitously expressed in humans and mice. A mutation in its encoding gene causes hypertension in humans, which is associated with abnormal ion homeostasis. WNK1 is critical for in vitro decidualization in human endometrial stromal cel...
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doaj-9cd769b8a4f046ccbce9ce99614ee48b2021-08-03T00:11:58ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-11-01522WNK1 regulates uterine homeostasis and its ability to support pregnancyRu-pin Alicia ChiTianyuan WangChou-Long HuangSan-pin WuSteven L. YoungJohn P. LydonFrancesco J. DeMayoWNK1 (with no lysine [K] kinase 1) is an atypical kinase protein ubiquitously expressed in humans and mice. A mutation in its encoding gene causes hypertension in humans, which is associated with abnormal ion homeostasis. WNK1 is critical for in vitro decidualization in human endometrial stromal cells, thereby demonstrating its importance in female reproduction. Using a mouse model, WNK1 was ablated in the female reproductive tract to define its in vivo role in uterine biology. Loss of WNK1 altered uterine morphology, causing endometrial epithelial hyperplasia, adenomyotic features, and a delay in embryo implantation, ultimately resulting in compromised fertility. Combining transcriptomic, proteomic, and interactomic analyses revealed a potentially novel regulatory pathway whereby WNK1 represses AKT phosphorylation through protein phosphatase 2A (PP2A) in endometrial cells from both humans and mice. We show that WNK1 interacted with PPP2R1A, the alpha isoform of the PP2A scaffold subunit. This maintained the levels of PP2A subunits and stabilized its activity, which then dephosphorylated AKT. Therefore, loss of WNK1 reduced PP2A activity, causing AKT hypersignaling. Using FOXO1 as a readout of AKT activity, we demonstrate that there was escalated FOXO1 phosphorylation and nuclear exclusion, leading to a disruption in the expression of genes that are crucial for embryo implantation.https://doi.org/10.1172/jci.insight.141832Reproductive biology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ru-pin Alicia Chi Tianyuan Wang Chou-Long Huang San-pin Wu Steven L. Young John P. Lydon Francesco J. DeMayo |
spellingShingle |
Ru-pin Alicia Chi Tianyuan Wang Chou-Long Huang San-pin Wu Steven L. Young John P. Lydon Francesco J. DeMayo WNK1 regulates uterine homeostasis and its ability to support pregnancy JCI Insight Reproductive biology |
author_facet |
Ru-pin Alicia Chi Tianyuan Wang Chou-Long Huang San-pin Wu Steven L. Young John P. Lydon Francesco J. DeMayo |
author_sort |
Ru-pin Alicia Chi |
title |
WNK1 regulates uterine homeostasis and its ability to support pregnancy |
title_short |
WNK1 regulates uterine homeostasis and its ability to support pregnancy |
title_full |
WNK1 regulates uterine homeostasis and its ability to support pregnancy |
title_fullStr |
WNK1 regulates uterine homeostasis and its ability to support pregnancy |
title_full_unstemmed |
WNK1 regulates uterine homeostasis and its ability to support pregnancy |
title_sort |
wnk1 regulates uterine homeostasis and its ability to support pregnancy |
publisher |
American Society for Clinical investigation |
series |
JCI Insight |
issn |
2379-3708 |
publishDate |
2020-11-01 |
description |
WNK1 (with no lysine [K] kinase 1) is an atypical kinase protein ubiquitously expressed in humans and mice. A mutation in its encoding gene causes hypertension in humans, which is associated with abnormal ion homeostasis. WNK1 is critical for in vitro decidualization in human endometrial stromal cells, thereby demonstrating its importance in female reproduction. Using a mouse model, WNK1 was ablated in the female reproductive tract to define its in vivo role in uterine biology. Loss of WNK1 altered uterine morphology, causing endometrial epithelial hyperplasia, adenomyotic features, and a delay in embryo implantation, ultimately resulting in compromised fertility. Combining transcriptomic, proteomic, and interactomic analyses revealed a potentially novel regulatory pathway whereby WNK1 represses AKT phosphorylation through protein phosphatase 2A (PP2A) in endometrial cells from both humans and mice. We show that WNK1 interacted with PPP2R1A, the alpha isoform of the PP2A scaffold subunit. This maintained the levels of PP2A subunits and stabilized its activity, which then dephosphorylated AKT. Therefore, loss of WNK1 reduced PP2A activity, causing AKT hypersignaling. Using FOXO1 as a readout of AKT activity, we demonstrate that there was escalated FOXO1 phosphorylation and nuclear exclusion, leading to a disruption in the expression of genes that are crucial for embryo implantation. |
topic |
Reproductive biology |
url |
https://doi.org/10.1172/jci.insight.141832 |
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