Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells.
Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells.
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DOI：
10.3390/biom11091382
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发表时间：
2021-09-18
期刊：
影响因子：
5.5
通讯作者：
Gupta MB
中科院分区：
文献类型：
--
作者：
Nandi P;Jang CE;Biggar K;Halari CD;Jansson T;Gupta MB
胰岛素样生长因子-1(IGF-1)在妊娠期间的生物利用度受IGF结合蛋白(IGFBP-1)及其磷酸化控制，IGFBP-1可增强IGFBP-1与生长因子的亲和力。蜕膜是母体IGFBP-1的主要来源；然而，调节蜕膜IGFBP-1分泌/磷酸化的机制尚不清楚。利用早孕胎盘蜕膜化的原代人子宫内膜间质细胞(HESCs)，我们验证了mTORC1信号机制将缺氧与蜕膜IGFBP-1分泌/磷酸化联系起来的假说。低氧抑制雷帕霉素作用靶点(p-P70-S6K/Thr389，−47%，p=0.038；p-4E-bp1/Thr70，−55%，p=0.012)，升高IGFBP-1(总数，+35%，p=0.005；磷酸化，Ser101/+82%，p=0.018；Ser119/+88%，p=0.039；Ser169/+157%，p=0.019)。靶向平行反应监测-质谱仪(PRM-MS)还显示低氧条件下IGFBP-1双磷酸化(pSer98+Ser101；pSer169+Ser174)显著增加。IGFBP-1过度磷酸化抑制IGF1受体自身磷酸化/Tyr1135(−为29%，p=0.002)。此外，沉默结节性硬化症复合体2(TSC2)激活了mTORc1(p-P70-S6K/Thr389，+68%，p=0.038；p-4E-bp1/Thr70，+30%，p=0.002)，并降低了总的/位点特异性的IGFBP-1的磷酸化。重要的是，TSC2 siRNA阻止了缺氧时mTORC1的抑制和分泌/位点特异性IGFBP-1磷酸化的增加。PRM-MS显示伴随蛋白激酶自身磷酸化的改变(CK2/Tyr182；PKC/Thr497；PKC/Ser657)。总体而言，mTORC1信号在机制上将缺氧与原发性HESC中IGFBP-1的分泌/磷酸化联系在一起，暗示蜕膜mTORC1抑制是将子宫胎盘缺氧与胎儿生长受限联系起来的新机制。
Insulin-like growth factor-1 (IGF-1) bioavailability in pregnancy is governed by IGF binding protein (IGFBP-1) and its phosphorylation, which enhances the affinity of IGFBP-1 for the growth factor. The decidua is the predominant source of maternal IGFBP-1; however, the mechanisms regulating decidual IGFBP-1 secretion/phosphorylation are poorly understood. Using decidualized primary human endometrial stromal cells (HESCs) from first-trimester placenta, we tested the hypothesis that mTORC1 signaling mechanistically links hypoxia to decidual IGFBP-1 secretion/phosphorylation. Hypoxia inhibited mechanistic target of rapamycin (mTORC1) (p-P70-S6K/Thr389, −47%, p = 0.038; p-4E-BP1/Thr70, −55%, p = 0.012) and increased IGFBP-1 (total, +35%, p = 0.005; phosphorylated, Ser101/+82%, p = 0.018; Ser119/+88%, p = 0.039; Ser 169/+157%, p = 0.019). Targeted parallel reaction monitoring-mass spectrometry (PRM-MS) additionally demonstrated markedly increased dual IGFBP-1 phosphorylation (pSer98+Ser101; pSer169+Ser174) in hypoxia. IGFBP-1 hyperphosphorylation inhibited IGF-1 receptor autophosphorylation/ Tyr1135 (−29%, p = 0.002). Furthermore, silencing of tuberous sclerosis complex 2 (TSC2) activated mTORC1 (p-P70-S6K/Thr389, +68%, p = 0.038; p-4E-BP1/Thr70, +30%, p = 0.002) and reduced total/site-specific IGFBP-1 phosphorylation. Importantly, TSC2 siRNA prevented inhibition of mTORC1 and the increase in secretion/site-specific IGFBP-1 phosphorylation in hypoxia. PRM-MS indicated concomitant changes in protein kinase autophosphorylation (CK2/Tyr182; PKC/Thr497; PKC/Ser657). Overall, mTORC1 signaling mechanistically links hypoxia to IGFBP-1 secretion/phosphorylation in primary HESC, implicating decidual mTORC1 inhibition as a novel mechanism linking uteroplacental hypoxia to fetal growth restriction.
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影响因子：
5.2
作者：
Allard JB;Duan C
通讯作者：
Duan C
影响因子：
4.8
作者：
Abu Shehab, Majida;Damerill, Ian;Gupta, Madhulika B.
通讯作者：
Gupta, Madhulika B.
亮氨酸剥夺引起的 IGFBP-1 过度磷酸化是由 AAR 途径介导的。
影响因子：
4.1
作者：
Malkani N;Jansson T;Gupta MB
通讯作者：
Gupta MB
影响因子：
--
作者：
Damerill, Ian;Biggar, Kyle K.;Gupta, Madhulika B.
通讯作者：
Gupta, Madhulika B.
影响因子：
4.1
作者：
Abu Shehab, Majida;Biggar, Kyle;Gupta, Madhulika B.
通讯作者：
Gupta, Madhulika B.