Effects of ATP-competitive and function-selective ERK inhibitors on airway smooth muscle cell proliferation
Effects of ATP-competitive and function-selective ERK inhibitors on airway smooth muscle cell proliferation
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DOI：
10.1096/fj.201900680r
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发表时间：
2019-10-01
期刊：
影响因子：
4.8
通讯作者：
Deshpande, Deepak A.
中科院分区：
文献类型：
--
作者：
Defnet, Amy E.;Huang, Weiliang;Deshpande, Deepak A.
气道平滑肌（ASM）细胞质量和分泌功能增加是气道炎症性疾病（例如哮喘）的特征。迄今为止，还没有有效的疗法来对抗 ASM 细胞增殖，ASM 细胞增殖会导致支气管收缩和气道阻塞。血小板源性生长因子 (PDGF) 等生长因子和 ERK1/2 的激活是哮喘中 ASM 细胞增殖和气道重塑的主要调节因子。然而，鉴于 ERK1/2 的普遍表达和多种功能，使用 ATP 竞争性抑制剂完全抑制 ERK1/2 可能会导致不良的脱靶效应。或者，我们已经鉴定出旨在靶向底物对接位点并充当 ERK1/2 信号传导的功能选择性抑制剂的化合物。在此，我们证明功能选择性和 ATP 竞争性 ERK1/2 抑制剂均可有效抑制 ASM 细胞中 PDGF 介导的增殖、胶原蛋白生成和 IL-6 分泌。蛋白质组学分析表明，两种类型的抑制剂对减少与气道重塑相关的 TGF-β 和 IL-6 信号传导相关的蛋白质具有相似的作用。然而，与 ATP 竞争性抑制剂相比，功能选择性 ERK1/2 抑制剂引起的蛋白质表达变化较小。这些研究为开发功能选择性 ERK1/2 抑制剂以通过 ERK1/2 信号传导的明确调节来减轻哮喘气道重塑提供了分子基础。-Defnet, A. E., Huang, W., Polischak, S., Yadav, S. K., Kane, M. A., Shapiro, P., Deshpande, D. A. ATP 竞争性和功能选择性 ERK 抑制剂对气道的影响平滑肌细胞增殖。
Increased airway smooth muscle (ASM) cell mass and secretory functions are characteristics of airway inflammatory diseases, such as asthma. To date, there are no effective therapies to combat ASM cell proliferation, which contributes to bronchoconstriction and airway obstruction. Growth factors such as platelet-derived growth factor (PDGF) and the activation of the ERK1/2 are major regulators of ASM cell proliferation and airway remodeling in asthma. However, given the ubiquitous expression and multiple functions of ERK1/2, complete inhibition of ERK1/2 using ATP-competitive inhibitors may lead to unwanted off-target effects. Alternatively, we have identified compounds that are designed to target substrate docking sites and act as function-selective inhibitors of ERK1/2 signaling. Here, we show that both function-selective and ATP-competitive ERK1/2 inhibitors are effective at inhibiting PDGF-mediated proliferation, collagen production, and IL-6 secretion in ASM cells. Proteomic analysis revealed that both types of inhibitors had similar effects on reducing proteins related to TGF-beta and IL-6 signaling that are relevant to airway remodeling. However, function-selective ERK1/2 inhibitors caused fewer changes in protein expression compared with ATP-competitive inhibitors. These studies provide a molecular basis for the development of function-selective ERK1/2 inhibitors to mitigate airway remodeling in asthma with defined regulation of ERK1/2 signaling.-Defnet, A. E., Huang, W., Polischak, S., Yadav, S. K., Kane, M. A., Shapiro, P., Deshpande, D. A. Effects of ATP-competitive and function-selective ERK inhibitors on airway smooth muscle cell proliferation.