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Tyrosine phosphatase SHP2 in ovarian granulosa cells balances follicular development by inhibiting PI3K/AKT signaling
Xiaoli Wei1 , Lanping Zheng1 , Yingpu Tian1 , Haibin Wang2 , Youqiang Su3 , Gensheng Feng4 , Chao Wang5,* , Zhongxian Lu1,2,*
1School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen 361005, China
2Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen University, Xiamen 361102, China
3State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
4Department of Pathology, Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093, USA
5State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
*Correspondence to:Chao Wang , Zhongxian Lu ,
J Mol Cell Biol, Volume 14, Issue 7, July 2022, mjac048,
Keyword: tyrosine phosphatase, SHP2, granulosa cell, follicular development, PI3K/AKT signaling

In mammals, the growth and maturation of oocytes within growing follicles largely depends on ovarian granulosa cells (GCs) in response to gonadotropin stimulation. Many signals have been shown to regulate GC proliferation and apoptosis. However, whether the tyrosine phosphatase SHP2 is involved remains unclear. In this study, we identified the crucial roles of SHP2 in modulating GC proliferation and apoptosis. The production of both mature oocytes and pups was increased in mice with Shp2 specifically deleted in ovarian GCs via Fshr-Cre. Shp2 deletion simultaneously promoted GC proliferation and inhibited GC apoptosis. Furthermore, Shp2 deficiency promoted, while Shp2 overexpression inhibited, the proliferation of cultured primary mouse ovarian GCs and the human ovarian granulosa-like tumor cell line KGN in vitro. Shp2 deficiency promoted follicule-stimulating hormone (FSH)-activated phosphorylation of AKT in vivo. SHP2 deficiency reversed the inhibitory effect of hydrogen peroxide (H2O2) on AKT activation in KGN cells. H2O2 treatment promoted the interaction between SHP2 and the p85 subunit of PI3K in KGN cells. Therefore, SHP2 in GCs may act as a negative modulator to balance follicular development by suppressing PI3K/AKT signaling. The novel function of SHP2 in modulating proliferation and apoptosis of GCs provides a potential therapeutic target for the clinical treatment of follicle developmental dysfunction.