期刊
MOLECULAR MEDICINE REPORTS
卷 14, 期 1, 页码 263-270出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2016.5216
关键词
beta-arrestin2; Src; extracellular signal-regulated kinase; tumor necrosis factor-related apoptosis-inducing ligand; apoptosis
资金
- Natural Science Research Project of Anhui Colleges and Universities [KJ2016SD59]
- College Outstanding Young Talent Support Program Key Projects [gxyqZD2016173]
- Natural Science Research Project of Anhui Provincial Education Department [KJ2013B311]
- National Nature Science Foundation of China [31301171]
- Anhui Province Key Laboratory of active biological macromolecules [1306C083008]
beta-arrestins, including beta-arrestin1 and beta-arrestin2, two ubiquitously expressed members of the arrestin family in various types of tissue, are adaptor proteins that modulate the desensitization and trafficking of seven membrane-spanning receptors. Recently, beta-arrestins have been shown to bind to numerous signaling molecules, including c-Src and mitogen-activated protein kinase family members. In addition, accumulating evidence has suggested that beta-arrestins are involved in the anti-apoptosis signaling pathway by associating with kinases, such as Akt and ERK, and altering their activities. However, the role of beta-arrestins in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis remains unclear. In the present study, beta-arrestin2, but not beta-arrestin1, was observed to modulate TRAIL-triggered HepG2 cell apoptosis by regulating activation of the Src-extracellular signal-regulated kinase (ERK) signaling pathway. Using overexpression and RNA interference experiments, beta-arrestin2 was demonstrated to prevent TRAIL-induced HepG2 cell apoptosis. Additionally, beta-arrestin2 exerted an additive effect on TRAIL-induced activation of Src and ERK. Furthermore, downregulating beta-arrestin2 expression attenuated the TRAIL-induced activation of Src and ERK survival signaling and enhanced TRAIL-induced apoptosis. PP2, a pharmacological inhibitor of Src, reduced activation of the Src-ERK signaling pathway and enhanced TRAIL-induced HepG2 cell apoptosis. Co-immunoprecipitation experiments demonstrated a physical association between beta-arrestin2 and Src, and TRAIL stimulation resulted in enhanced quantities of the beta-arrestin2/Src complex. A notable interaction was identified between beta-arrestin2 and death receptors (DR) 4 and 5, but only in the presence of TRAIL stimulation. To the best of our knowledge, these findings are the first to demonstrate that beta-arrestin2 mediates TRAIL-induced apoptosis by combing with DRs and Src, and regulates the activation of Src-ERK signaling in HepG2 cells. It is hypothesized that the formation of a signaling complex comprising DR, beta-arrestin2 and Src is required for the action of TRAIL on HepG2 cell apoptosis, which provides a novel insight into analyzing the effects of beta-arrestin2 on protecting cells from TRAIL-induced apoptosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据