Journal
LIFE SCIENCE ALLIANCE
Volume 5, Issue 10, Pages -Publisher
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.202201409
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Funding
- Istituto Fondazione di Oncologia Molecolare Imaging Unit [AIRC-5x1000, 21052, 23820]
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MET is an oncogene that encodes a tyrosine kinase receptor for hepatocyte growth factor (HGF). When MET is mutated or amplified, it becomes a driver for cancer. The most common mutation in the MET gene affects the splicing sites of exon 14, leading to the deletion of a receptor domain. Our analysis showed that MET Delta 14 is dependent on HGF for kinase activation and has enhanced cellular protection and migration.
MET is an oncogene encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF). Upon ligand binding, MET activates multiple signal transducers, including PI3K/AKT, STAT3, and MAPK. When mutated or amplified, MET becomes a driver for the onset and progression of cancer. The most frequent mutations in the MET gene affect the splicing sites of exon 14, leading to the deletion of the receptor's juxtamembrane domain (MET Delta 14). It is currently believed that, as in gene amplification, MET Delta 14 kinase is constitutively active. Our analysis of MET in carcinoma cell lines showed that MET Delta 14 strictly depends on HGF for kinase activation. Compared with wt MET, Delta 14 is sensitive to lower HGF concentrations, with more sustained kinase response. Using three different models, we have demonstrated that MET Delta 14 activation leads to robust phosphorylation of AKT, leading to a distinctive transcriptomic signature. Functional studies revealed that Delta 14 activation is predominantly responsible for enhanced protection from apoptosis and cellular migration. Thus, the unique HGF-dependent Delta 14 oncogenic activity suggests consideration of HGF in the tumour microenvironment to select patients for clinical trials.
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