SHP2 participates in decidualization by activating ERK to maintain normal nuclear localization of progesterone receptor

by Selleckchem | Aug 22 2023

Decidualization is the process of conversion of endometrial stromal cells (ESCs) into decidual stromal cells (DSCs), which is caused by progesterone production that begins during the luteal phase of the menstrual cycle and then increases throughout pregnancy dedicated to support embryonic development. Decidualization deficiency is closely associated with various pregnancy complications, such as recurrent miscarriage (RM). Here, we reported that Src-homology-2-containing phospho-tyrosine phosphatase (SHP2), a key regulator in the signal transduction process downstream of various receptors, plays an indispensable role in decidualization. SHP2 expression was upregulated during decidualization. SHP2 inhibitor RMC-4550 and shRNA mediated SHP2 reduction resulted in a decreased level of phosphorylation of ERK and aberrant cytoplasmic localization of progesterone receptor (PR), coinciding with reduced expression of IGFBP1 and various other target genes of decidualization. Solely inhibiting ERK activity recapitulated these observations. Administration of RMC-4550 led to decidualization deficiency and embryo absorption in mouse. Moreover, reduced expression of SHP2 was detected in decidua of RM patients. Our results revealed that SHP2 is key to PR's nuclear localization, thereby indispensable for decidualization and that reduced expression of SHP2 might be engaged in the pathogenesis of RM.

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Decidualization is a crucial process in the menstrual cycle and pregnancy, involving the transformation of endometrial stromal cells (ESCs) into decidual stromal cells (DSCs). This conversion is primarily driven by the production of progesterone, which begins during the luteal phase of the menstrual cycle and continues to increase throughout pregnancy, aiming to support embryonic development. Deficiencies in decidualization have been closely associated with various pregnancy complications, including recurrent miscarriage (RM).

In a recent study, the researchers reported the significance of a protein called Src-homology-2-containing phospho-tyrosine phosphatase (SHP2) in the process of decidualization. SHP2 is known to be a key regulator in the signal transduction pathway downstream of several receptors. The researchers found that SHP2 expression was upregulated during decidualization, indicating its potential importance in this process.

To investigate the role of SHP2 in decidualization, the researchers utilized an SHP2 inhibitor called RMC-4550 and employed shRNA to reduce SHP2 levels. They observed that inhibiting SHP2 activity led to a decrease in the phosphorylation of ERK, a key protein involved in signaling pathways, and abnormal cytoplasmic localization of the progesterone receptor (PR). This coincided with reduced expression of insulin-like growth factor binding protein 1 (IGFBP1) and other genes associated with decidualization.

The researchers further demonstrated the impact of inhibiting SHP2 in vivo by administering RMC-4550 to mice. This resulted in decidualization deficiency and embryo absorption, suggesting the crucial role of SHP2 in supporting successful pregnancy.

Furthermore, the study found reduced expression of SHP2 in the decidua of patients with recurrent miscarriage, indicating a potential involvement of SHP2 deficiency in the development of this condition.

In summary, the study provides evidence that SHP2 is a key regulator in decidualization. It is necessary for the nuclear localization of the progesterone receptor (PR), which is essential for decidualization. The study also suggests that reduced expression of SHP2 may be involved in the pathogenesis of recurrent miscarriage. These findings contribute to our understanding of the molecular mechanisms underlying decidualization and pregnancy complications, potentially opening new avenues for therapeutic interventions in the future.