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WNK1 regulates uterine homeostasis and its ability to support pregnancy.

Publication ,  Journal Article
Chi, R-PA; Wang, T; Huang, C-L; Wu, S-P; Young, SL; Lydon, JP; DeMayo, FJ
Published in: JCI insight
November 2020

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.

Duke Scholars

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Published In

JCI insight

DOI

EISSN

2379-3708

ISSN

2379-3708

Publication Date

November 2020

Volume

5

Issue

22

Start / End Page

141832

Related Subject Headings

  • WNK Lysine-Deficient Protein Kinase 1
  • Uterus
  • Transcriptome
  • Reproduction
  • Proto-Oncogene Proteins c-akt
  • Proteome
  • Protein Phosphatase 2
  • Pregnancy
  • Phosphorylation
  • Mice, Knockout
 

Citation

APA
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ICMJE
MLA
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Chi, R.-P., Wang, T., Huang, C.-L., Wu, S.-P., Young, S. L., Lydon, J. P., & DeMayo, F. J. (2020). WNK1 regulates uterine homeostasis and its ability to support pregnancy. JCI Insight, 5(22), 141832. https://doi.org/10.1172/jci.insight.141832
Chi, Ru-Pin Alicia, Tianyuan Wang, Chou-Long Huang, San-Pin Wu, Steven L. Young, John P. Lydon, and Francesco J. DeMayo. “WNK1 regulates uterine homeostasis and its ability to support pregnancy.JCI Insight 5, no. 22 (November 2020): 141832. https://doi.org/10.1172/jci.insight.141832.
Chi R-PA, Wang T, Huang C-L, Wu S-P, Young SL, Lydon JP, et al. WNK1 regulates uterine homeostasis and its ability to support pregnancy. JCI insight. 2020 Nov;5(22):141832.
Chi, Ru-Pin Alicia, et al. “WNK1 regulates uterine homeostasis and its ability to support pregnancy.JCI Insight, vol. 5, no. 22, Nov. 2020, p. 141832. Epmc, doi:10.1172/jci.insight.141832.
Chi R-PA, Wang T, Huang C-L, Wu S-P, Young SL, Lydon JP, DeMayo FJ. WNK1 regulates uterine homeostasis and its ability to support pregnancy. JCI insight. 2020 Nov;5(22):141832.

Published In

JCI insight

DOI

EISSN

2379-3708

ISSN

2379-3708

Publication Date

November 2020

Volume

5

Issue

22

Start / End Page

141832

Related Subject Headings

  • WNK Lysine-Deficient Protein Kinase 1
  • Uterus
  • Transcriptome
  • Reproduction
  • Proto-Oncogene Proteins c-akt
  • Proteome
  • Protein Phosphatase 2
  • Pregnancy
  • Phosphorylation
  • Mice, Knockout