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

Abstract

利用动物胚胎植入模型和转基因模式动物，吕忠显研究团队发现Shp2在子宫内膜细胞中特异敲除，可造成胚胎植入完全失败，雌性小鼠不育；机制研究发现，缺失Shp2阻断了子宫内膜基质细胞中的雌激素信号活性。进一步研究发现，Shp2并不像在其他细胞中主要定位于细胞质发挥功能，而是需要进入细胞核中结合雌激素受体，募集并调控Src信号蛋白对雌激素受体（ER）的活化，最终影响雌激素受体靶蛋白的转录，其中包括对子宫接受态建立关键的孕激素受体（PR）的表达调控。Shp2能调控多种生长因子和细胞因子信号，该研究证明Shp2介导其它信号促进雌激素受体ER活性发挥的结果，将能促进胚胎植入信号调控网络的理解，对于认识雌、孕激素调控内膜容受态的建立也提供新的思路。 这些工作是与厦大医学院王海滨教授领导的生殖研究团队、中国农业大学王超博士课题组共同完成的。【Abstract】Estrogen and progesterone coupled with locally produced signaling molecules are essential for embryo implantation. However, the hierarchical landscape of the molecular pathways that governs this process remains largely unexplored. Here we show that the protein tyrosine phosphatase Shp2, a positive transducer of RTK signaling, is predominately localized in the nuclei in the periimplantation mouse uterus. Uterine-specific deletion of Shp2 exhibits reduced progesterone receptor (PR) expression and progesterone resistance, which derails normal uterine receptivity, leading to complete implantation failure in mice. Notably, the PR expression defects are attributed to the limited estrogen receptor α (ERα) activation in uterine stroma. Further analysis reveals that nuclear Shp2, rather than cytosolic Shp2, promotes the ERα transcription activity. This function is achieved by enhancing the Src kinase-mediated ERα tyrosine phosphorylation, which facilitates ERα binding to Pgr promoter in an ERK-independent manner in periimplantation uteri. Besides uncovering a regulatory mechanism, this study could be clinically relevant to dysfunctional ERα-caused endometrial disorders in women.This work was supported in parts by the National Natural Science Foundation (81130009, 81330017, and 81490744 to H.W.; 81601285 to S.K.; and 31471106 to S.Z.)