Center of Clinical Research, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
Nat Commun. 2018 Jun 27;9(1):2504. doi: 10.1038/s41467-018-04936-9.
To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation.
迄今为止，胶质瘤中组成性信号转导和转录激活因子 3（STAT3）激活的分子机制在很大程度上尚不清楚。在这项研究中，我们报告了 Smad6 在神经胶质瘤细胞核中过表达，这与患者预后不良相关，并通过负调控激活 STAT3 的蛋白抑制剂（PIAS3）来调节 STAT3 活性。在机制上，Smad6 直接与 PIAS3 相互作用，这种相互作用是通过 Smad6 的 Mad 同源结构域 2（MH2）和 PIAS3 的环结构域介导的。Smad6 招募 Smurf1 促进 PIAS3 的泛素化和降解，这也依赖于 Smad6 的 MH2 结构域和 PY 基序。因此，Smad6 减少了 PIAS3 介导的 STAT3 抑制作用，促进了神经胶质瘤细胞的生长和干细胞样细胞的起始。此外，Smad6 的 MH2 转导蛋白恢复了 PIAS3 的表达，随后降低了神经胶质瘤的发生。综上所述，核 Smad6 通过诱导 PIAS3 降解和随后的 STAT3 活性上调，增强了神经胶质瘤的发展。
