title: EGF stimulates the activation of EGF receptors and the selective activation of major signaling pathways during mitosis.
abstract: Mitosis and epidermal growth factor (EGF) receptor (EGFR) are both targets for cancer therapy. The role of EGFR signaling in mitosis has been rarely studied and poorly understood. The limited studies indicate that the activation of EGFR and downstream signaling pathways is mostly inhibited during mitosis. However, we recently showed that EGFR is phosphorylated in response to EGF stimulation in mitosis. Here we studied EGF-induced EGFR activation and the activation of major signaling pathways downstream of EGFR during mitosis. We showed that EGFR was strongly activated by EGF during mitosis as all the five major tyrosine residues including Y992, Y1045, Y1068, Y1086, and Y1173 were phosphorylated to a level similar to that in the interphase. We further showed that the activated EGFR is able to selectively activate some downstream signaling pathways while avoiding others. Activated EGFR is able to activate PI3K and AKT2, but not AKT1, which may be responsible for the observed effects of EGF against nocodazole-induced cell death. Activated EGFR is also able to activate c-Src, c-Cbl and PLC-γ1 during mitosis. However, activated EGFR is unable to activate ERK1/2 and their downstream substrates RSK and Elk-1. While it activated Ras, EGFR failed to fully activate Raf-1 in mitosis due to the lack of phosphorylation at Y341 and the lack of dephosphorylation at pS259. We conclude that contrary to the dogma, EGFR is activated by EGF during mitosis. Moreover, EGFR-mediated cell signaling is regulated differently from the interphase to specifically serve the needs of the cell in mitosis.
authors.affiliation: Department of Medical Genetics, and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Wee
authors.affiliation: Department of Medical Genetics, and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Huaiping
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Medical Genetics, and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Medical Genetics, and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Yuluan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medical Genetics, and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Electronic address: zhixiang.wang@ualberta.ca.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000081247:CSK Tyrosine-Protein Kinase; D002455:Cell Division; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007399:Interphase; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D015739:Nocodazole / Q000494:pharmacology / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015739:Nocodazole; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D051057:Proto-Oncogene Proteins c-akt; D050721:Proto-Oncogene Proteins c-cbl; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: AKT; Cell cycle; Cell signaling; EGF receptor; ERK; Mitosis