Estrogen Regulates the Expression and Localization of YAP in the Uterus of Mice

Abstract

The dynamics of uterine endometrium is important for successful establishment and maintenance of embryonic implantation and development, along with extensive cell differentiation and proliferation. The tissue event is precisely and complicatedly regulated as several signaling pathways are involved including two main hormones, estrogen and progesterone signaling. We previously showed a novel signaling molecule, Serine/threonine protein kinase 3/4 (STK3/4), which is responded to hormone in the mouse uterine epithelium. However, the role and regulation of its target, YES-associated protein (YAP) remains unknown. In this study, we investigated the expression and regulation of YAP in mouse endometrium. We found that YAP was periodically expressed in the endometrium during the estrous cycle. Furthermore, periodic expression of YAP was shown to be related to the pathway under hormone treatment. Interestingly, estrogen was shown to positively modulate YAP via endometrial epithelial receptors. In addition, the knockdown of YAP showed that YAP regulated various target genes in endometrial cells. The knockdown of YAP down-regulated numerous targets including ADAMTS1, AMOT, AMOTL1, ANKRD1, CTNNA1, MCL1. On the other hand, the expressions of AREG and AXL were increased by its knockdown. These findings imply that YAP responds via Hippo signaling under various intrauterine signals and is considered to play a role in the expression of factors important for uterine endometrium dynamic regulation.

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“…STK3 is serine/threonine kinase 3 and plays an important role in the female reproductive system. Previous studies have shown that STK3 responded to E and P hormones in the mouse uterine epithelium ( Moon et al, 2019 , 2022 ). Moreover, STK3 was indicated as one of the key candidate genes for litter size performance in goats ( E et al, 2019 ).…”

cfDNA Methylation Profiles and T-Cell Differentiation in Women with Endometrial Polyps

“…STK3 is a key molecule in the Hippo pathway, which is highly expressed in the endometrium [ 39 ]. The activity of the STK3/ Hippo pathway is activated through estrogen and its receptor [ 40 , 41 ], and then regulates angiogenesis, cell proliferation and differentiation, and apoptosis in the endometrium, thus increasing the risk of EP. Moreover, the STK3/Hippo pathway participates in immune regulation [ 42 ].…”

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“…In addition to the liver, estrogen is also a vital regulatory hormone in the ovaries. Using estrogen in ovariectomized mice upregulates the phosphorylation of YAP in a time‐dependent manner, then decreases the YAP‐targeted genes expression in endometrial cells 57 . Moreover, ERα also plays a role in regulating Src‐induced YAP activation.…”

“…Using estrogen in ovariectomized mice upregulates the phosphorylation of YAP in a time‐dependent manner, then decreases the YAP‐targeted genes expression in endometrial cells. 57 Moreover, ERα also plays a role in regulating Src‐induced YAP activation. In ERα overexpression MCF‐7 cell, the upregulated ERα can phosphorylate YAP at Tyr357 and then enhance the expression of its downstream gene connective tissue growth factor (CTGF) through enabling Src tyrosine kinase.…”