Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein

Abstract 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 METΔ7−8. METΔ7−8 is located predominantly in the cytosol and is constitutively active. The auto-activating nature of METΔ7−8, in combination with a lack of transmembrane localization, renders METΔ7−8 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.
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Source: Cancer Cell - Category: Cancer & Oncology Source Type: research
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Source: Clinical Nuclear Medicine - Category: Nuclear Medicine Tags: Original Articles Source Type: research
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Source: Phytomedicine - Category: Drugs & Pharmacology Source Type: research
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Source: Journal of Photochemistry and Photobiology B: Biology - Category: Speech-Language Pathology Source Type: research
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Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Non-coding RNA profiling by array Homo sapiens Source Type: research
No abstract available
Source: Neurology Today - Category: Neurology Tags: Disease Mechanisms Source Type: research
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Source: Nano Letters - Category: Nanotechnology Authors: Source Type: research
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Source: BMC Cancer - Category: Cancer & Oncology Authors: Tags: Research article Source Type: research
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Source: Journal of Neuro-Oncology - Category: Cancer & Oncology Source Type: research
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