Int J Biol Sci 2019; 15(1):114-126. doi:10.7150/ijbs.28679

Research Paper

COPI-Mediated Nuclear Translocation of EGFRvIII Promotes STAT3 Phosphorylation and PKM2 Nuclear Localization

Mingzhi Zhang1,#, Haojie Sun2,#, Yue Deng3, Ming Su1, Shiruo Wei1, Peipei Wang3, Lanlan Yu4, Jinwen Liu4, Jinhai Guo4, Xuan Wang5, Xu Han5, Qihua He6✉, Li Shen1✉

1. Department of Cell Biology, Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
2. Neuroscience Research Institute, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
3. Beijing Cellonis Biotechnologies Co. Ltd, Zhongguancun Bio-Medicine Park, Beijing, People's Republic of China
4. Beijing DongFang YaMei Gene Science and Technology Research Institute, Beijing, People's Republic of China
5. Research Center of Artificial Organ and Tissue Engineering, Second Department of Hepatobiliary Surgery, ZhuJiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China
6. Medical and Health Analytical Center, Peking University Health Science Center, People's Republic of China
# These authors have contributed equally to this work

Abstract

As a non-ligand-dependent activation protein, EGFRvIII is the most common mutant of EGFR, and its existence or especially its nuclear translocation in tumors can exacerbate the malignancy. Compared with the nuclear translocation of EGFR, which has been studied extensively, the specific mechanism by which EGFRvIII undergoes nuclear translocation has not yet been reported. Here, we found that EGFRvIII eventually reached the nucleus with the involvement of the Golgi and endoplasmic reticulum (ER) in glioma cells. In this process, syntaxin-6 was responsible for the identification and transport of EGFRvIII on Golgi. We also demonstrated that COPI mediated the reverse transport of EGFRvIII from the Golgi to ER, which process was also important for EGFRvIII's nuclear accumulation. EGFRvIII's nuclear translocation can significantly promote STAT3 phosphorylation and PKM2 nuclear localization. Finally, we showed that EGFRvIII's nuclear translocation obviously induced the growth of gliomas in an intracranial xenotransplantation experiment. These data suggested that searching methods that inhibit EGFRvIII entry into the nucleus will be effective glioma treatments.

Keywords: EGFRvIII, nuclear translocation, Syntaxin-6, COPI, PKM2 nuclear localization

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How to cite this article:
Zhang M, Sun H, Deng Y, Su M, Wei S, Wang P, Yu L, Liu J, Guo J, Wang X, Han X, He Q, Shen L. COPI-Mediated Nuclear Translocation of EGFRvIII Promotes STAT3 Phosphorylation and PKM2 Nuclear Localization. Int J Biol Sci 2019; 15(1):114-126. doi:10.7150/ijbs.28679. Available from http://www.ijbs.com/v15p0114.htm