1. Academic Validation
  2. Targeting EGFR-dependent tumors by disrupting an ARF6-mediated sorting system

Targeting EGFR-dependent tumors by disrupting an ARF6-mediated sorting system

  • Nat Commun. 2022 Oct 12;13(1):6004. doi: 10.1038/s41467-022-33788-7.
Huiling Guo # 1 Juan Wang # 2 Su Ren # 1 Lang-Fan Zheng # 2 Yi-Xuan Zhuang 1 Dong-Lin Li 1 Hui-Hui Sun 1 Li-Ying Liu 1 Changchuan Xie 1 Ya-Ying Wu 1 Hong-Rui Wang 1 Xianming Deng 1 3 Peng Li 2 4 5 Tong-Jin Zhao 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 2 State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
  • 3 State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, 361102, China.
  • 4 School of life sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
  • 5 Shanghai Qi Zhi Institute, Shanghai, 200232, China.
  • 6 State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai, 200438, China. zhaotj@fudan.edu.cn.
  • 7 Shanghai Qi Zhi Institute, Shanghai, 200232, China. zhaotj@fudan.edu.cn.
  • # Contributed equally.
Abstract

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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