title: Regulation of EGFR nanocluster formation by ionic protein-lipid interaction.
abstract: The abnormal activation of epidermal growth factor receptor (EGFR) is strongly associated with a variety of human cancers but the underlying molecular mechanism is not fully understood. By using direct stochastic optical reconstruction microscopy (dSTORM), we find that EGFR proteins form nanoclusters in the cell membrane of both normal lung epithelial cells and lung cancer cells, but the number and size of clusters significantly increase in lung cancer cells. The formation of EGFR clusters is mediated by the ionic interaction between the anionic lipid phosphatidylinositol-4,5-bisphosphate (PIP2) in the plasma membrane and the juxtamembrane (JM) region of EGFR. Disruption of EGFR clustering by PIP2 depletion or JM region mutation impairs EGFR activation and downstream signaling. Furthermore, JM region mutation in constitutively active EGFR mutant attenuates its capability of cell transformation. Collectively, our findings highlight the key roles of anionic phospholipids in EGFR signaling and function, and reveal a novel mechanism to explain the aberrant activation of EGFR in cancers.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Xingdong
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Tong
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Shi
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Lunyi
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Computer Science and Information Technology, Northeast Normal University, Changchun, Jilin 130117, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
authors.forename: Junguang
authors.initials: J
authors.lastname: Jiang
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Chenqi
authors.initials: C
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
authors.forename: Hongda
authors.initials: H
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007477:Ions / Q000737:chemistry; D008168:Lung / Q000166:cytology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D049329:Nanostructures / Q000737:chemistry*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D007477:Ions; D019269:Phosphatidylinositol 4,5-Diphosphate; D066246:ErbB Receptors