Published in:
Open Access
01-07-2015 | Original Paper
Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein
Authors:
Anna C. Navis, Sanne A. M. van Lith, Sander M. J. van Duijnhoven, Maaike de Pooter, Bahar Yetkin-Arik, Pieter Wesseling, Wiljan J. A. J. Hendriks, Hanka Venselaar, Marco Timmer, Patricia van Cleef, Paul van Bergen en Henegouwen, Myron G. Best, Thomas D. Wurdinger, Bastiaan B. J. Tops, William P. J. Leenders
Published in:
Acta Neuropathologica
|
Issue 1/2015
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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.