期刊
ACTA NEUROPATHOLOGICA
卷 130, 期 1, 页码 131-144出版社
SPRINGER
DOI: 10.1007/s00401-015-1420-5
关键词
MET; Glioma; Mutation; Protein localization; Genetic deletion; Auto-active; Intracellular location; Biomarker
资金
- internal RUCO research grant
- Stichting STOPhersentumoren.nl
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 Delta 7-8. MET Delta 7-8 is located predominantly in the cytosol and is constitutively active. The auto-activating nature of MET Delta 7-8, in combination with a lack of transmembrane localization, renders MET Delta 7-8 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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