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

Huiling Guo, Juan Wang, Su Ren, Lang-Fan Zheng, Yi-Xuan Zhuang, Dong-Lin Li, Hui-Hui Sun, Li-Ying Liu, Changchuan Xie, Ya-Ying Wu, Hong-Rui Wang, Xianming Deng, Peng Li and Tong-Jin Zhao ()
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Huiling Guo: School of Life Sciences, Xiamen University, Xiamen
Juan Wang: Zhongshan Hospital, Fudan University
Su Ren: School of Life Sciences, Xiamen University, Xiamen
Lang-Fan Zheng: Zhongshan Hospital, Fudan University
Yi-Xuan Zhuang: School of Life Sciences, Xiamen University, Xiamen
Dong-Lin Li: School of Life Sciences, Xiamen University, Xiamen
Hui-Hui Sun: School of Life Sciences, Xiamen University, Xiamen
Li-Ying Liu: School of Life Sciences, Xiamen University, Xiamen
Changchuan Xie: School of Life Sciences, Xiamen University, Xiamen
Ya-Ying Wu: School of Life Sciences, Xiamen University, Xiamen
Hong-Rui Wang: School of Life Sciences, Xiamen University, Xiamen
Xianming Deng: School of Life Sciences, Xiamen University, Xiamen
Peng Li: Zhongshan Hospital, Fudan University
Tong-Jin Zhao: Zhongshan Hospital, Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33788-7

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