Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein
| Autor: | Navis, Anna C, van Lith, Sanne A M, van Duijnhoven, Sander M J, de Pooter, Maaike, Yetkin-Arik, Bahar, Wesseling, Pieter, Hendriks, Wiljan J A J, Venselaar, Hanka, Timmer, Marco, van Cleef, Patricia, van Bergen En Henegouwen, Paul, Best, Myron G, Wurdinger, Thomas D, Tops, Bastiaan B J, Leenders, William P J, Celbiologie, Sub Cell Biology |
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| Přispěvatelé: | Neurosurgery, Celbiologie, Sub Cell Biology, Pathology, CCA - Oncogenesis |
| Rok vydání: | 2015 |
| Předmět: |
Male
Protein Conformation Pyridines Messenger RNA Messenger/metabolism Messenger/metabolism medicine.disease_cause Castration-Resistant Proto-Oncogene Proteins c-met/antagonists & inhibitors Exon Mice Taverne Anilides Non-U.S. Gov't Sequence Deletion Medicine(all) Pyridines/pharmacology Mutation Tumor Hepatocyte Growth Factor Research Support Non-U.S. Gov't Sarcoma Glioma Proto-Oncogene Proteins c-met Ligand (biochemistry) Protein subcellular localization prediction Transmembrane protein Anilides/pharmacology Intracellular location Prostatic Neoplasms Castration-Resistant MET Female Tyrosine kinase Antibodies/metabolism Clinical Neurology Hepatocyte Growth Factor/metabolism Sarcoma/genetics Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] Biology Research Support Antibodies Pathology and Forensic Medicine Cell Line Cellular and Molecular Neuroscience Prostatic Neoplasms Castration-Resistant/genetics Cell Line Tumor medicine Journal Article Animals Humans splice RNA Messenger Protein Kinase Inhibitors Original Paper Protein localization Carcinoma Prostatic Neoplasms Genetic deletion Biomarker Molecular biology Carcinoma/genetics Castration-Resistant/genetics Protein Kinase Inhibitors/pharmacology Glioma/drug therapy Cancer research RNA Neurology (clinical) Neoplasm Grading Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] Neoplasm Transplantation Auto-active |
| Zdroj: | Navis, A C, van Lith, S A M, van Duijnhoven, S M J, de Pooter, M, Yetkin-Arik, B, Wesseling, P, Hendriks, W J A J, Venselaar, H, Timmer, M, van Cleef, P, Henegouwen, P V E, Best, M G, Würdinger, T, Tops, B B J & Leenders, W P J 2015, ' Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein ', Acta Neuropathologica, vol. 130, no. 1, pp. 131-144 . https://doi.org/10.1007/s00401-015-1420-5 Acta Neuropathologica Acta neuropathologica, 130(1), 131-44. Springer Verlag Acta Neuropathologica, 130(1), 131-144. Springer Verlag Acta Neuropathologica, 130(1), 131. Springer Verlag Acta Neuropathologica, 130, 131-44 Acta Neuropathologica, 130, 1, pp. 131-44 |
| ISSN: | 0001-6322 |
| Popis: | Contains fulltext : 153045.pdf (Publisher’s version ) (Open Access) MET has gained interest as a therapeutic target for a number of malignancies because of its involvement in tumorigenesis, invasion and metastasis. At present, a number of inhibitors, both antibodies against MET or its ligand hepatocyte growth factor, and small molecule MET tyrosine kinase inhibitors are in clinical trials. We here describe a novel variant of MET that is expressed in 6 % of high-grade gliomas. Characterization of this mutation in a glioma cell line revealed that it consists of an intronic deletion, resulting in a splice event connecting an intact splice donor site in exon 6 with the next splice acceptor site being that of exon 9. The encoded protein lacks parts of the extracellular IPT domains 1 and 2, encoded by exons 7 and 8, resulting in a novel pseudo-IPT and is named MET(Delta7-8). MET(Delta7-8) is located predominantly in the cytosol and is constitutively active. The auto-activating nature of MET(Delta7-8), in combination with a lack of transmembrane localization, renders MET(Delta7-8) not targetable using antibodies, although the protein is efficiently deactivated by MET-specific tyrosine kinase inhibitors. Testing of MET-expressing tumors for the presence of this variant may be important for treatment decision making. |
| Databáze: | OpenAIRE |
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