Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China.
PLoS Genet. 2021 Apr 26;17(4):e1009514. doi: 10.1371/journal.pgen.1009514. eCollection 2021 Apr.
The regulatory subunits (P60 in insects, P85 in mammals) determine the activation of the catalytic subunits P110 in phosphatidylinositol 3-kinases (PI3Ks) in the insulin pathway for cell proliferation and body growth. However, the regulatory subunits also promote apoptosis via an unclear regulatory mechanism. Using Helicoverpa armigera, an agricultural pest, we showed that H. armigera P60 (HaP60) was phosphorylated under insulin-like peptides (ILPs) regulation at larval growth stages and played roles in the insulin/ insulin-like growth factor (IGF) signaling (IIS) to determine HaP110 phosphorylation and cell membrane translocation; whereas, HaP60 was dephosphorylated and its expression increased under steroid hormone 20-hydroxyecdysone (20E) regulation during metamorphosis. Protein tyrosine phosphatase non-receptor type 6 (HaPTPN6, also named tyrosine-protein phosphatase corkscrew-like isoform X1 in the genome) was upregulated by 20E to dephosphorylate HaP60 and HaP110. 20E blocked HaP60 and HaP110 translocation to the cell membrane and reduced their interaction. The phosphorylated HaP60 mediated a cascade of protein phosphorylation and forkhead box protein O (HaFOXO) cytosol localization in the IIS to promote cell proliferation. However, 20E, via G protein-coupled-receptor-, ecdysone receptor-, and HaFOXO signaling axis, upregulated HaP60 expression, and the non-phosphorylated HaP60 interacted with phosphatase and tensin homolog (HaPTEN) to induce apoptosis. RNA interference-mediated knockdown of HaP60 and HaP110 in larvae repressed larval growth and apoptosis. Thus, HaP60 plays dual functions to promote cell proliferation and apoptosis by changing its phosphorylation status under ILPs and 20E regulation, respectively.
调节亚基（昆虫中的 P60，哺乳动物中的 P85）决定了磷脂酰肌醇 3-激酶（PI3Ks）的催化亚基 P110 在胰岛素途径中的激活，从而促进细胞增殖和身体生长。然而，调节亚基也通过不清楚的调节机制促进细胞凋亡。利用农业害虫棉铃虫，我们表明，在幼虫生长阶段，胰岛素样肽（ILPs）调节下，棉铃虫 P60（HaP60）被磷酸化，并在胰岛素/胰岛素样生长因子（IGF）信号（IIS）中发挥作用，以决定 HaP110 的磷酸化和细胞膜易位；而在变态期间，类固醇激素 20-羟基蜕皮酮（20E）调节下，HaP60 去磷酸化且其表达增加。蛋白酪氨酸磷酸酶非受体型 6（HaPTPN6，在基因组中也称为酪氨酸蛋白磷酸酶 corkscrew-like 异构体 X1）被 20E 上调以去磷酸化 HaP60 和 HaP110。20E 阻断 HaP60 和 HaP110 向细胞膜的易位，并减少它们的相互作用。磷酸化的 HaP60 介导了一系列蛋白磷酸化和叉头框蛋白 O（HaFOXO）在 IIS 中的细胞质定位，以促进细胞增殖。然而，20E 通过 G 蛋白偶联受体、蜕皮激素受体和 HaFOXO 信号轴上调 HaP60 的表达，非磷酸化的 HaP60 与磷酸酶和张力蛋白同源物（HaPTEN）相互作用诱导细胞凋亡。幼虫中的 HaP60 和 HaP110 的 RNA 干扰介导的敲低抑制了幼虫的生长和凋亡。因此，HaP60 通过在 ILPs 和 20E 调节下改变其磷酸化状态，分别发挥促进细胞增殖和凋亡的双重功能。
