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Nuclear Shp2 directs normal embryo implantation via facilitating the ERα tyrosine phosphorylation by the Src kinase
Hao Ran1, Shuangbo Kong2,3, Shuang Zhang4
1State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, People's Republic of China.
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.
Insights
The protein tyrosine phosphatase Shp2 is crucial for embryo implantation by regulating progesterone receptor expression. Nuclear Shp2 enhances estrogen receptor activity, ensuring uterine receptivity and successful pregnancy in mice.
Area of Science:
- Reproductive biology
- Molecular endocrinology
- Signal transduction
Background:
- Embryo implantation requires coordinated action of estrogen, progesterone, and local signaling molecules.
- The molecular pathways governing uterine receptivity are not fully understood.
- Protein tyrosine phosphatase Shp2 is a key regulator of receptor tyrosine kinase (RTK) signaling.
Purpose of the Study:
- To investigate the role of Shp2 in the molecular regulation of embryo implantation.
- To elucidate the mechanism by which Shp2 influences uterine receptivity.
- To explore the clinical relevance of Shp2 in endometrial disorders.
Main Methods:
- Generated uterine-specific Shp2 knockout mice.
- Assessed progesterone receptor (PR) and estrogen receptor alpha (ERα) expression and activity.
- Investigated the interaction between Shp2, ERα, Src kinase, and the Pgr promoter.
- Utilized techniques to examine nuclear vs. cytosolic Shp2 localization and function.
Main Results:
- Uterine-specific deletion of Shp2 led to reduced PR expression and progesterone resistance, causing implantation failure.
- Shp2 deficiency impaired ERα activation in uterine stroma, contributing to PR expression defects.
- Nuclear Shp2 enhances ERα transcriptional activity by promoting Src kinase-mediated ERα tyrosine phosphorylation.
- This ERα activation facilitates ERα binding to the Pgr promoter in an ERK-independent manner.
Conclusions:
- Nuclear Shp2 plays a critical role in regulating uterine receptivity and embryo implantation.
- Shp2 acts as a key mediator between ERα signaling and PR expression.
- This mechanism highlights a potential therapeutic target for ERα-related endometrial disorders.