Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Sci Rep. 2017 Jun 23;7(1):4174. doi: 10.1038/s41598-017-04528-5.
Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3β (GSK3β) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal-regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3β, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity. Inhibition of ERK1/2 in Tsc2 cells-a model of TS-rescues GSK3β activity and protein synthesis levels, thus highlighting ERK1/2 as a potential therapeutic target for the treatment of TS.
结节性硬化症（TS）是一种多器官常染色体显性遗传病，其特征主要为神经发育缺陷和良性肿瘤的存在。TS 病理学是由结节性硬化复合物（TSC）基因突变引起的，与胰岛素抵抗、糖原合酶激酶 3β（GSK3β）活性降低、雷帕霉素靶蛋白复合物 1（mTORC1）的激活以及随后的蛋白质合成增加有关。在这里，我们表明细胞外信号调节激酶（ERK1/2）对胰岛素刺激作出反应，并整合胰岛素信号以磷酸化并因此使 GSK3β失活，导致独立于 Akt/mTORC1 活性的蛋白质合成增加。在 Tsc2 细胞（TS 的模型）中抑制 ERK1/2 可恢复 GSK3β活性和蛋白质合成水平，从而突出 ERK1/2 作为治疗 TS 的潜在治疗靶标。
