Targeting EGFR-dependent tumors by disrupting an ARF6-mediated sorting system.
Targeting EGFR-dependent tumors by disrupting an ARF6-mediated sorting system.
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通过破坏 ARF6 介导的分选系统来靶向 EGFR 依赖性肿瘤
DOI：
10.1038/s41467-022-33788-7
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发表时间：
2022-10-12
影响因子：
16.6
通讯作者：
Zhao, Tong-Jin
中科院分区：
文献类型：
--
作者：
Guo, Huiling;Wang, Juan;Ren, Su;Zheng, Lang-Fan;Zhuang, Yi-Xuan;Li, Dong-Lin;Sun, Hui-Hui;Liu, Li-Ying;Xie, Changchuan;Wu, Ya-Ying;Wang, Hong-Rui;Deng, Xianming;Li, Peng;Zhao, Tong-Jin
由于EGFR过度表达或突变导致的EGFR异常激活与许多类型肿瘤的不良预后相关。在这里，我们表明，阻断将EGFR导向质膜的分选系统是治疗EGFR依赖性肿瘤的有效策略。我们发现，EGFR棕榈酰化DHHC 13是至关重要的质膜定位，并确定ARF 6在这一过程中的关键因素。N-肉豆蔻酰化的ARF 6通过脂质-脂质相互作用识别棕榈酰化的EGFR，募集胞外复合物以促进EGFR从高尔基体出芽，并促进EGFR以GTP结合形式转运至质膜。为了评估这种分选系统的治疗潜力，我们设计了一种细胞渗透性肽，N-肉豆蔻酰化GKVL-TAT，并发现它有效地破坏EGFR的质膜定位，并显着抑制EGFR依赖性肿瘤的进展。我们的发现揭示了棕榈酰化如何指导蛋白质分选的潜在机制，并提供了一种管理EGFR依赖性肿瘤的潜在策略。
Aberrant activation of EGFR due to overexpression or mutation is associated with poor prognosis in many types of tumors. Here we show that blocking the sorting system that directs EGFR to plasma membrane is a potent strategy to treat EGFR-dependent tumors. We find that EGFR palmitoylation by DHHC13 is critical for its plasma membrane localization and identify ARF6 as a key factor in this process. N-myristoylated ARF6 recognizes palmitoylated EGFR via lipid-lipid interaction, recruits the exocyst complex to promote EGFR budding from Golgi, and facilitates EGFR transporting to plasma membrane in a GTP-bound form. To evaluate the therapeutic potential of this sorting system, we design a cell-permeable peptide, N-myristoylated GKVL-TAT, and find it effectively disrupts plasma membrane localization of EGFR and significantly inhibits progression of EGFR-dependent tumors. Our findings shed lights on the underlying mechanism of how palmitoylation directs protein sorting and provide an potential strategy to manage EGFR-dependent tumors.
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影响因子：
2.9
作者：
Antonny, B;BeraudDufour, S;Chabre, M
通讯作者：
Chabre, M
影响因子：
46.9
作者：
Fredriksson, S;Gullberg, M;Landegren, U
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影响因子：
48
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影响因子：
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作者：
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影响因子：
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作者：
Sigismund S;Avanzato D;Lanzetti L
通讯作者：
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