Identification of a Novel PP2A Regulator, WNK1, as Critical For Uterine Function

WNK1 is critical for uterine function as a mediator of stromal cell decidualization . Here, we employed a mouse model with conditional WNK1 ablation from the female reproductive tract to define its role in uterine biology. Loss of WNK1 altered uterine morphology, causing endometrial epithelial hyperplasia, adenomyosis and a delay in embryo implantation, ultimately resulting in compromised fertility. Mechanistic investigations through transcriptomic and proteomic approaches uncovered the regulatory role of WNK1 in controlling the PP2A-AKT-FOXO1 signaling axis. We show that WNK1 interacts directly with PPP2R1A, which is crucial for PP2A phosphatase activity. PP2A phosphatase in turn dephosphorylates AKT, thereby reducing its inhibitory effect on FOXO1. This permits the nuclear entry of FOXO1 to transcriptionally regulate implantation-associated genes. Our findings revealed a novel function of WNK1 in regulating AKT-FOXO1 post-translational modification, and demonstrated that this signaling pathway is critical in normal uterine physiology and pregnancy.