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

2015/04/10 by Anna C. Navis, Sanne A. M. van Lith, Sander M. J. van Duijnhoven +16 · 24 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Alternative splicing #Biology #Cancer Mechanisms and Therapy #Cancer research #Carcinogenesis #Exon #Gene #Genetics #Glioma #Liver physiology and pathology #Microtubule and mitosis dynamics #Molecular biology #Mutation #RNA splicing #Receptor #Signal transduction #Transmembrane protein #Tyrosine kinase

paper · pdf · doi:10.1007/s00401-015-1420-5

openalex publication_date 2015/04/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05

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 MET(Δ7-8). MET(Δ7-8) is located predominantly in the cytosol and is constitutively active. The auto-activating nature of MET(Δ7-8), in combination with a lack of transmembrane localization, renders MET(Δ7-8) 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.

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