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

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

35 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)131-144
Aantal pagina's14
TijdschriftActa Neuropathologica
Volume130
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 17 jul. 2015
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein'. Samen vormen ze een unieke vingerafdruk.

Citeer dit