Nox4 redox regulation of PTP1B contributes to the proliferation and migration of glioblastoma cells by modulating tyrosine phosphorylation of coronin-1C |
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| Institution: | 1. Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan 390-8621;2. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA;1. Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada;2. Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada;3. Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;4. Department of Psychology, University of Alberta, Edmonton, Alberta, Canada;1. Department of Microbiology and Immunology, Western University, London, Ontario, Canada;2. Department of Surgery, Western University, London, Ontario, Canada;3. Matthew Mailing Centre for Translational Transplant Studies, London Health Sciences Centre, London, Ontario, Canada;4. Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada;5. Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Ontario, Canada;1. The Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, 4811, Australia;2. The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia;3. School of Surgery, University of Western Australia, Perth, WA, Australia;4. School of Medicine and Pharmacology, University of Western Australia, Perth, Australia;5. Department of Neurology, Sir Charles Gardiner Hospital, Nedlands, Perth, Australia;6. Department of Geriatric Medicine, Royal Perth Hospital, Perth, Australia;7. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia;8. WA Centre for Health and Ageing, Centre for Medical Research, Perth, Australia;9. Department of Psychiatry, Royal Perth Hospital, Perth, Australia;10. Department of Diabetes and Endocrinology, Fiona Stanley Hospital, Perth, Australia;11. Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, QLD, Australia |
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| Abstract: | Glioblastoma multiforme is a common primary brain tumor in adults and one of the most devastating human cancers. Reactive oxygen species (ROS) generated by NADPH oxidase (Nox) 4 have recently been a focus of attention in the study of glioblastomas, but the molecular mechanisms underlying the actions of Nox4 remain elusive. In this study, we demonstrated that silencing of Nox4 expression by Nox4-targeted siRNA suppressed cell growth and motility of glioblastoma U87 cells, indicating the involvement of Nox4. Furthermore, Nox4-derived ROS oxidized and inactivated protein tyrosine phosphatase (PTP):1B: PTP1B in its active form downregulates cell proliferation and migration. By affinity purification with the substrate-trapping mutant of PTP1B, tyrosine-phosphorylated coronin-1C was identified as a substrate of PTP1B. Its tyrosine phosphorylation level was suppressed by Nox4 inhibition, suggesting that tyrosine phosphorylation of coronin-1C is regulated by the Nox4–PTP1B pathway. Finally, ablation of coronin-1C attenuated the proliferative and migratory activity of the cells. Collectively, these findings reveal that Nox4-mediated redox regulation of PTP1B serves as a modulator, in part through coronin-1C, of the growth and migration of glioblastoma cells, and provide new insight into the mechanistic aspect of glioblastoma malignancy. |
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| Keywords: | NADPH oxidase (Nox)4 Glioblastoma PTP1B Coronin-1C Cell proliferation Cell migration |
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