Decrease in SHP-1 Enhances Myometrium Remodeling via FAK Activation Leading to Labor

• Published in: American journal of physiology: endocrinology and metabolism 2020-06, Vol.318 (6), p.E930-E942
• Main Authors: Chen, Huai-Yan, Gao, Ling-Tong, Yuan, Jian-Qiang, Zhang, Yu-Ji, Liu, Pei, Wang, Gang, Ni, Xin, Liu, Wei-Na, Gao, Lu
• Format: Article
• Language: English
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/AJPENDO.00068.2020

Preterm birth is one of the most common complications during human pregnancy, and associated with a dramatic switch within the uterus from quiescence to contractility. However, the mechanisms underlying uterine remodeling are largely unknown. Protein kinases and phosphatases play critical roles in regulating the phosphorylation of proteins involved in the smooth muscle cell functions. In the present study, we found that src-homology phosphatase type-1 (SHP-1, PTPN6) was significantly decreased in human myometrium in labor compared with that not in labor. Timed-pregnant mice injected intraperitoneally with the specific SHP-1 inhibitor, PTPI-1, manifested significantly preterm labor, with enriched plasmalemmal dense plaques between myometrial cells and increased phosphorylation at Tyr397 and Tyr576/577 sites of focal adhesion kinase (FAK) in myometrial cells, which remained to the time of labor, whereas the phosphorylation levels of ERK1/2 and PI3K showed a rapid increase upon PTPI-1 injection, but fell back to normal at the time of labor. The Tyr576/577 in FAK played an important role in the interaction between FAK and SHP-1. Knockdown of SHP-1 dramatically increased the spontaneous contraction of HUSMCs, which was reversed by co-infection of a FAK-knockdown lentivirus. PGF a downregulated SHP-1 via PLCβ-PKC-NF-kB or PI3K-NF-kB pathways, suggesting the regenerative downregulation of SHP-1 enhances the uterine remodeling and plasticity by activating FAK and subsequent focal adhesion pathway, which eventually facilitates myometrium contraction and leads to labor. The study examined mechanisms that underlie the initiation of labor, and interventions for modulation of SHP-1 may provide a potential strategy for preventing preterm birth.