Decrease in SHP-1 enhances myometrium remodeling via FAK activation leading to labor
- 1 June 2020
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Endocrinology and Metabolism
- Vol. 318 (6), E930-E942
- https://doi.org/10.1152/ajpendo.00068.2020
Abstract
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. PGF2a 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.Keywords
Funding Information
- National Natural Science Foundation of China (81622020 & 81771608)
- National Key Research and Development Project (2017YFC1001404)
- Program of Shanghai Academic/Technology Research Leader (18XD1405100)
- "Dawn" Program of Shanghai Education Commission (17SG36)
- Program of Shanghai Subject Chief Scientist (2017BR017)
- The Program for Professor of Special Appointment(Eastern Scholar) at Shanghai Institutions of Higher Learning
This publication has 60 references indexed in Scilit:
- SHP-1–Pyk2–Src Protein Complex and p38 MAPK Pathways Independently Regulate IL-10 Production in Lipopolysaccharide-Stimulated MacrophagesThe Journal of Immunology, 2013
- Periodic Mechanical Stress Stimulates the FAK Mitogenic Signal in Rat Chondrocytes Through ERK1/2 ActivityCellular Physiology and Biochemistry, 2013
- CEACAM1 Negatively Regulates IL-1β Production in LPS Activated Neutrophils by Recruiting SHP-1 to a SYK-TLR4-CEACAM1 ComplexPLoS Pathogens, 2012
- Focal Adhesion Kinase–Related Nonkinase Inhibits Vascular Smooth Muscle Cell Invasion by Focal Adhesion Targeting, Tyrosine 168 Phosphorylation, and Competition for p130 Cas BindingArteriosclerosis, Thrombosis, and Vascular Biology, 2011
- Myosin II activity regulates vinculin recruitment to focal adhesions through FAK-mediated paxillin phosphorylationThe Journal of cell biology, 2010
- Prostaglandin F2α-F-prostanoid receptor regulates CXCL8 expression in endometrial adenocarcinoma cells via the calcium–calcineurin–NFAT pathwayBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2009
- Reduced expression of CRH receptor type 1 in upper segment human myometrium during labourReproductive Biology and Endocrinology, 2009
- Expression of the calcium-activated potassium channel in upper and lower segment human myometrium during pregnancy and parturitionReproductive Biology and Endocrinology, 2009
- Labor-Associated Gene Expression in the Human Uterine Fundus, Lower Segment, and CervixPLoS Medicine, 2006
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001