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High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation

BACKGROUND: PTPRZ1‐MET (ZM) is a critical genetic alteration driving the progression of lower‐grade glioma. Glioma patients harboring ZM could benefit from MET inhibitors. According to the remarkable role of ZM as a driver of glioma progression and indicator of MET inhibitor sensitivity, it is neces...

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Autores principales: Huang, Ruoyu, Liu, Yanwei, Wang, Kuanyu, Wang, Zheng, Zhang, Chuanbao, Zhang, Wei, Zhao, Zheng, Li, Guanzhang, Huang, Lijie, Chang, Yuanhao, Zeng, Fan, Jiang, Tao, Hu, Huimin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025647/
https://www.ncbi.nlm.nih.gov/pubmed/33645009
http://dx.doi.org/10.1111/cns.13627
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author Huang, Ruoyu
Liu, Yanwei
Wang, Kuanyu
Wang, Zheng
Zhang, Chuanbao
Zhang, Wei
Zhao, Zheng
Li, Guanzhang
Huang, Lijie
Chang, Yuanhao
Zeng, Fan
Jiang, Tao
Hu, Huimin
author_facet Huang, Ruoyu
Liu, Yanwei
Wang, Kuanyu
Wang, Zheng
Zhang, Chuanbao
Zhang, Wei
Zhao, Zheng
Li, Guanzhang
Huang, Lijie
Chang, Yuanhao
Zeng, Fan
Jiang, Tao
Hu, Huimin
author_sort Huang, Ruoyu
collection PubMed
description BACKGROUND: PTPRZ1‐MET (ZM) is a critical genetic alteration driving the progression of lower‐grade glioma. Glioma patients harboring ZM could benefit from MET inhibitors. According to the remarkable role of ZM as a driver of glioma progression and indicator of MET inhibitor sensitivity, it is necessary to detect this alteration even when it presents in glioma with relatively fewer copies. METHODS: Herein, we proposed that ZM could be detected with a high‐sensitive method of reverse transcriptase PCR with 50 amplification cycles. Via this newly proposed detection method, we depicted the incidence preference of ZM fusion in a cohort of 485 glioma patients. To further explore the oncogenic nature of ZM, we predicated the protein structure alteration of MET kinase brought by its fusion partner. RESULTS: The incidence of ZM fusions was much higher than previous report. ZM fusions exhibited a striking preference in lower‐grade glioma and secondary glioblastoma. By contrast, none of patients with primary glioblastoma was detected harboring ZM fusion. In each of the four variants of ZM, the fusion partner segment of MET contained a remarkable coiled‐coil motif. In glioma cells expressing ZM, MET kinase could be activated in a ligand‐independent manner, which might be contributed by the special coiled‐coil structure brought by the fusion partner. Corresponding to the 3D structural analysis and cell line experiment, the ZM positive clinical specimens showed hyperactivations of MET signaling. CONCLUSIONS: ZM fusions are critical drivers of glioma progression and effective target of MET inhibitor. Early detection could be performed with a high‐sensitive method of reverse transcriptase PCR. The hyperactivations of MET signaling driving glioma progression might be contributed by a ligand‐independent activation enabled by the protein structure modification of extracellular domain of MET in ZM fusions.
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spelling pubmed-80256472021-04-13 High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation Huang, Ruoyu Liu, Yanwei Wang, Kuanyu Wang, Zheng Zhang, Chuanbao Zhang, Wei Zhao, Zheng Li, Guanzhang Huang, Lijie Chang, Yuanhao Zeng, Fan Jiang, Tao Hu, Huimin CNS Neurosci Ther Original Articles BACKGROUND: PTPRZ1‐MET (ZM) is a critical genetic alteration driving the progression of lower‐grade glioma. Glioma patients harboring ZM could benefit from MET inhibitors. According to the remarkable role of ZM as a driver of glioma progression and indicator of MET inhibitor sensitivity, it is necessary to detect this alteration even when it presents in glioma with relatively fewer copies. METHODS: Herein, we proposed that ZM could be detected with a high‐sensitive method of reverse transcriptase PCR with 50 amplification cycles. Via this newly proposed detection method, we depicted the incidence preference of ZM fusion in a cohort of 485 glioma patients. To further explore the oncogenic nature of ZM, we predicated the protein structure alteration of MET kinase brought by its fusion partner. RESULTS: The incidence of ZM fusions was much higher than previous report. ZM fusions exhibited a striking preference in lower‐grade glioma and secondary glioblastoma. By contrast, none of patients with primary glioblastoma was detected harboring ZM fusion. In each of the four variants of ZM, the fusion partner segment of MET contained a remarkable coiled‐coil motif. In glioma cells expressing ZM, MET kinase could be activated in a ligand‐independent manner, which might be contributed by the special coiled‐coil structure brought by the fusion partner. Corresponding to the 3D structural analysis and cell line experiment, the ZM positive clinical specimens showed hyperactivations of MET signaling. CONCLUSIONS: ZM fusions are critical drivers of glioma progression and effective target of MET inhibitor. Early detection could be performed with a high‐sensitive method of reverse transcriptase PCR. The hyperactivations of MET signaling driving glioma progression might be contributed by a ligand‐independent activation enabled by the protein structure modification of extracellular domain of MET in ZM fusions. John Wiley and Sons Inc. 2021-02-28 /pmc/articles/PMC8025647/ /pubmed/33645009 http://dx.doi.org/10.1111/cns.13627 Text en © 2021 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Huang, Ruoyu
Liu, Yanwei
Wang, Kuanyu
Wang, Zheng
Zhang, Chuanbao
Zhang, Wei
Zhao, Zheng
Li, Guanzhang
Huang, Lijie
Chang, Yuanhao
Zeng, Fan
Jiang, Tao
Hu, Huimin
High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation
title High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation
title_full High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation
title_fullStr High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation
title_full_unstemmed High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation
title_short High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation
title_sort high‐sensitive clinical diagnostic method for ptprz1‐met and the characteristic protein structure contributing to ligand‐independent met activation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025647/
https://www.ncbi.nlm.nih.gov/pubmed/33645009
http://dx.doi.org/10.1111/cns.13627
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