Physiological Significance Of Tyrosine Phosphatase Shp2during Embryo Implantation In Mice

Embryo implantation is one of the most important processes for early pregnancy. Embryo implantation failure is a major reason for pregnancy loss in women. Uterine receptivity is prerequisite for successful implantation. Although ovarian steroid hormones and their nuclear receptors PR and ER have been well demonstrated essential for embryo implantation, it remains largely unknown regarding the molecular mechanisms governing normal ER and PR functions during implantation.In the present study, we surprisingly found that Shp2, a ubiquitously expressed cytoplasmic protein-tyrosine phosphatase, is predominately localized in the nuclei of peri-implantation uterus with a spatiotemporal manner. Uterine-specific deletion of Shp2derails normal uterine receptivity, leading to a complete implantation failure. This compromised uterine receptivity exhibiting progesterone resistance upon Shp2depletion is seeded by limited ERa activation and thus reduced PR expression in uterine stroma. Further studies evidenced that nuclear Shp2, rather than cytosolic Shp2, physically interacts with ERa via SH2domain and functions in an unexpected phosphatase-and ERK-independent manner to ensure the ER activation. Moreover, we demonstrated that nuclear Shp2act as a positive regulator to facilitate ERa binding to the promoter of progesterone receptor PR, and subsequent recruitment of coactivators for transcriptional activation in vivo.Nonetheless, besides uncovering an absolutely novel function and mechanism of nuclear Shp2in ensuring normal ERa activation conducive to uterine receptivity and implantation, our findings have high clinical significance, since dysfunction ERa activition is often associated with multiple endometrial disorders.