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

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 kinasemediated 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.Shp2 | ERK signaling | Src kinase | estrogen receptor | uterine receptivity S uccessful implantation requires synchronization between an implantation-competent blastocyst and a receptive uterus. In humans, natural conception per cycle is poor (∼30%), and ∼75% of failed pregnancies are considered to be due to implantation failure (1). One-third of implantation failure is attributed to the embryo itself, whereas the remaining two-thirds appear to result from inadequate uterine receptivity (2). The endometrium enters into a receptive stage for blastocyst implantation only in a restricted time period termed "implantation window," which is dominated by precisely regulated proliferation and differentiation of endometrial epithelium and stroma under the influence of progesterone and estrogen (3).Estrogen and progesterone bind to the estrogen receptor (ER) and progesterone receptor (PR), respectively, coupled with specific cofactors to endure the optimal functions. The activity of these nuclear receptors is also regulated at the posttranslational level by various modifications, such as phosphorylation, which can influence the protein stability, interaction with the cofactors and DNA binding affinity. So far, a wide range of nuclear receptor cofactors have been identified to ensure the normal ER transcriptional activation, such as the well-known steroid receptor coactivator (SRC) family members, which bind with ERα in the chromatin to recruit the histone acetyltransferase p300 (P300) for transcriptional activation (4-6). It is conceivable that ordered and combinatorial recruitment of cofactors at a specific target promoter after ERα binding to DNA sequence was essential to ensure target gene transcription. Recent evidence shows that nuclear receptor coactivator 6 is essential for embryo implantation by maintaining the appropriate level and activity of uteri...

Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation

“…PR antagonist RU486 injection in the peri‐implantation period hampers uterine PDS and embryo implantation in wild‐type (WT) mice . According to the previous literature, implantation failure occurs in all types of mice with impaired uterine PDS . PR has two isoforms, PR‐A and PR‐B.…”

“…Intriguingly, the treatment with ER antagonist ICI‐182780 can rescue not only this hormonal signaling imbalance but also implantation failure . Protein tyrosine phosphatase SHP2, classic cytoplasmic protein, is present mainly in the nucleus of endometrial cells during implantation, and nuclear SHP2 enhances SRC kinase‐mediated ERα tyrosine phosphorylation, assists combining ERα with PR promoter, and proceeds the ERα transcription activity in the peri‐implantation period (Figure ).…”

Evidence For Hmgn2 Involvement in Mouse Embryo Implantation and Decidualization

“…Successful implantation requires the development of embryo to implantation-competent blastocyst and the synchronized transformation of uteri into a receptive stage [1-3]. Previous study has confirmed that Hmgn2 could play an important role in preimplantation embryonic development [12], but its biological function during embryo implantation remains unknown.…”

Nuclear Functions of the Tyrosine Kinase Src

“…Further studies have demonstrated that Src interacts with the estrogen receptor even in other cells such as the uterine cells and human breast cancer cells. Indeed, in the nuclei of uterine cells, active Src can phosphorylates estrogen receptor α (ERα) and enhances its transcriptional activity due to the activity of SHP2 (Src-Homology Protein2) [63]. SHP2, a protein encoded by the gene PTPN11, is generally located in the cytoplasm, but it is also known to translocate in the nucleus when DNA damage occurs [64].…”

“…SHP2, a protein encoded by the gene PTPN11, is generally located in the cytoplasm, but it is also known to translocate in the nucleus when DNA damage occurs [64]. SHP2 enhances Src tyrosine kinase activity by removing its inhibitory phosphorylation and Src, in turn, phosphorylates ERα, thus allowing its binding to the progesterone receptor promoter and driving its transcription [63].…”