GSE194382
MET?14 promotes a ligand-dependent, AKT-driven invasive growth
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 (survival/migration), STAT3 (differentiation), and MAPK (proliferation). 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 its "skipping" from mRNA and consequent deletion of the receptor's juxtamembrane domain (MET?14). It is currently believed that, as in gene amplification, MET?14 kinase is constitutively active.  Analysis of MET in carcinoma cell lines showed that MET?14 strictly depends on HGF for kinase activation. Compared to WT MET, ?14 is sensitive to lower HGF concentrations, with more sustained kinase response, ultimately leading to a robust phosphorylation of AKT, without affecting MAPK or STAT3. This altered kinase response leads to a distinctive transcriptomic signature. Functional studies revealed that ?14 activation is predominantly responsible for enhanced protection from apoptosis and cellular migration. Thus, the unique HGF-dependent ?14 oncogenic activity suggests consideration of HGF in the tumour microenvironment to select patients for clinical trials. Overall design: A549 and NCI-H596 cells linew were treated with HGF for  0, 3, 6 and 12 hours