Hippo Signaling in the Endometrium

Abstract

The uterus is essential for embryo implantation and fetal development. During the estrous cycle, the uterine endometrium undergoes dramatic remodeling to prepare for pregnancy. Angiogenesis is an essential biological process in endometrial remodeling. Steroid hormones regulate the series of events that occur during such remodeling. Researchers have investigated the potential factors, including angiofactors, involved in endometrial remodeling. The Hippo signaling pathway discovered in the 21st century, plays important roles in various cellular functions, including cell proliferation and cell death. However, its role in the endometrium remains unclear. In this review, we describe the female reproductive system and its association with the Hippo signaling pathway, as well as novel Hippo pathway genes and potential target genes.

Keywords: Hippo signaling; estrogen; estrous cycle; progesterone; uterus.

Figure 1

Hippo signaling pathway. YAP, a downstream target of the Hippo signaling pathway, activates the mammalian target of rapamycin (mTOR), a major regulator of cell growth. This suggests that the Hippo pathway, PTEN, and AKT are related. The stimulation of AKT and inhibition of the Hippo signaling pathway affect ovarian follicle growth. AKT activates dormant primordial follicles and promotes follicle growth by interfering with the Hippo signaling pathway by ovarian fragments. YAP regulates carcinogenesis in endometrial adenocarcinoma, and YAP expression correlated with the type of endometrial adenocarcinoma. In addition, the Hippo signaling pathway is a key downstream signaling branch of the G protein-coupled estrogen receptor (GPER) and plays a crucial role in breast tumorigenesis.

Figure 2

Role of P190A RhoGAP in various cellular processes. The interaction between P190A and p120-catenin at the cell-cell junction inhibits RhoA activity. CRAD (catenin-RhoGAP-association domain), a C-terminus domain of p120-catenin, interacts with P190A. CRAD depletion in p120-catenin of endothelial cells affects the transmembrane transduction of P190A and regulates endothelial permeability by increasing RhoA and decreasing the Rac1 signal. The crossover between cell-cell contact and cell-matrix adhesion is produced by the P190/P120-catenin complex to spatially regulate RhoA activity. The transient decrease in P190A levels during late mitosis in the cell cycle finely regulates RhoA activity required for cell division; P190A is also required to regulate spindle formation [23].

Figure 3

Interaction between P190A and Hippo signaling pathway in endometrial cancer cells. Under normal conditions, P190A induces YAP phosphorylation by crossing the Hippo signaling pathway through RhoA inhibition. When P190A is mutated, RhoA is abnormally activated, interfering with the activity of STK4 and MAP4K4/6/7, preventing the phosphorylation of LATS1/2, and triggering the transcriptional activation of YAP, resulting in the transcription of EMT-related target genes [81].