Biocenter, Gyeonggido Business and Science Accelerator, Suwon 16229, Korea.
Department of Physiology, Peripheral Neuropathy Research Center, Donga University Medical School, Busan 49201, Korea.
Molecules. 2021 Apr 8;26(8):2141. doi: 10.3390/molecules26082141.
Schwann cell differentiation involves a dynamic interaction of signaling cascades. However, much remains to be elucidated regarding the function of signaling molecules that differ depending on the context in which the molecules are engaged. Here, we identified a small molecule, dabrafenib, which promotes Schwann cell differentiation in vitro and exploited this compound as a pharmacological tool to understand the molecular mechanisms regulating Schwann cell differentiation. The results indicated that dabrafenib inhibited ERK phosphorylation and enhanced ErbB2 autophosphorylation and Akt phosphorylation, and the effects of dabrafenib on ErbB2 and Akt phosphorylation were phenocopied by pharmacological inhibition of the MEK-ERK signaling pathway. However, the small molecule inhibitors of MEK and ERK had no effect on the expression of Oct6 and EGR2, which are key transcription factors that drive Schwann cell differentiation. In addition, pharmacological inhibition of phosphatidylinositol-3-kinase (PI3K) almost completely interfered with dabrafenib-induced Schwann cell differentiation. These results suggest that the ErbB2-PI3K-Akt axis is required for the induction of Schwann cell differentiation by dabrafenib in vitro. Although additional molecules targeted by dabrafenib remain to be identified, our data provides insights into the crosstalk that exists between the MEK-ERK signaling pathway and the PI3K-Akt axis in Schwann cell differentiation.
许旺细胞分化涉及信号级联的动态相互作用。然而，对于根据参与分子的不同上下文而不同的信号分子的功能，仍有许多需要阐明。在这里，我们鉴定了一种小分子化合物 dabrafenib，它可促进体外许旺细胞分化，并利用该化合物作为药理学工具来了解调节许旺细胞分化的分子机制。结果表明，dabrafenib 抑制 ERK 磷酸化并增强 ErbB2 自身磷酸化和 Akt 磷酸化，dabrafenib 对 ErbB2 和 Akt 磷酸化的作用可被 MEK-ERK 信号通路的药理学抑制剂模拟。然而，MEK 和 ERK 的小分子抑制剂对驱动许旺细胞分化的关键转录因子 Oct6 和 EGR2 的表达没有影响。此外，PI3K 的药理学抑制剂几乎完全干扰 dabrafenib 诱导的许旺细胞分化。这些结果表明，ErbB2-PI3K-Akt 轴是 dabrafenib 在体外诱导许旺细胞分化所必需的。尽管 dabrafenib 靶向的其他分子仍有待确定，但我们的数据提供了对许旺细胞分化中 MEK-ERK 信号通路和 PI3K-Akt 轴之间存在的串扰的深入了解。
