Nuclear Shp2 directs normal embryo implantation via facilitating the ERα tyrosine phosphorylation by the Src kinase

Significance Dysfunctional uterine receptivity is responsible for approximately 70% of implantation failures. This periimplantation event is dominated by ovarian hormones progesterone and estrogen functioning through their corresponding receptors, PR and ER, coupled with locally produced signaling molecules. However, the hierarchical landscape of the molecular pathways that govern this process remains largely unexplored. Here we show that Shp2, a classic cytoplasmic protein, is mainly located in the nuclei in uterine cells at periimplantation. Further investigation revealed that nuclear Shp2 enhances the Src kinase-mediated ERα tyrosine phosphorylation, facilitates ERα binding to Pgr promoter, and thus promotes the ERα transcription activity in periimplantation uteri. Our findings have high clinical significance in identifying novel therapeutic targets for the aberrant uterine receptivity and implantation failure.