School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen 361005, China.
Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen University, Xiamen 361102, China.
J Mol Cell Biol. 2022 Sep 27;14(7). doi: 10.1093/jmcb/mjac048.
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.
在哺乳动物中，卵母细胞在生长卵泡中的生长和成熟在很大程度上取决于对促性腺激素刺激做出反应的卵巢颗粒细胞 (GC)。已经有许多信号被证明可以调节 GC 的增殖和凋亡。然而，酪氨酸磷酸酶 SHP2 是否参与其中尚不清楚。在这项研究中，我们确定了 SHP2 在调节 GC 增殖和凋亡中的关键作用。通过 Fshr-Cre 特异性删除卵巢 GC 中的 Shp2 ，小鼠的成熟卵母细胞和幼仔的产量增加。Shp2 缺失同时促进 GC 增殖并抑制 GC 凋亡。此外，Shp2 缺乏促进，而 Shp2 过表达抑制，体外培养的原代小鼠卵巢 GC 和人卵巢颗粒样肿瘤细胞系 KGN 的增殖。Shp2 缺乏促进体内卵泡刺激素 (FSH) 激活 AKT 的磷酸化。SHP2 缺乏逆转了过氧化氢 (H2O2) 对 KGN 细胞中 AKT 激活的抑制作用。H2O2 处理促进了 KGN 细胞中 SHP2 与 PI3K 的 p85 亚基之间的相互作用。因此，GC 中的 SHP2 可能作为一种负调节剂发挥作用，通过抑制 PI3K/AKT 信号通路来平衡卵泡发育。SHP2 调节 GC 增殖和凋亡的新功能为临床治疗卵泡发育功能障碍提供了一个潜在的治疗靶点。
