Crosstalk of Nemo-Like Kinase (NLK) and Yes-Associated Protein (YAP) Phosphorylation in Endometrial Epithelial Cells

The Hippo signaling pathway is an evolutionarily conserved pathway from Drosophila to humans. Although key elements of the Hippo signaling pathway are well-defined, the factors that control the transcriptional outcome of Hippo have yet to be fully elucidated. Until now, mainly in mammals, the Hippo signaling pathway has been focused on serine 127 (S127) of yes-associated protein (YAP), a key target gene. Recently, it has been shown that nemo-like kinase (NLK) can crosstalk with the Hippo pathway by phosphorylating an unknown new site of YAP. NLK transfers YAP serine 128 (S128) to the nucleus through dissociation of the 14-3-3 binding with YAP, promoting transcriptional activity. However, this is worth investigating as it has not been studied in the mammalian reproductive system and the precise mechanisms of signaling pathway crosstalk in endometrial cells that are dynamically altered by steroid hormones remain unclear. In this study, we found that expression of NLK and YAP S128 changes the expression site or extent of expression in the endometrium during the estrous cycle. Furthermore, we demonstrated that regulation of its expression proceeds through estrogen and its receptors. We have shown that these responses are triggered and regulated in uterine epithelial cells, suggesting that their expression plays a role in uterine dynamics during the estrous cycle, as does the hippocampal signaling pathway.