HGF/MET signaling pathway and most frequent alterations in NSCLC. The binding of HGF to MET leads to homodimerization and phosphorylation of the receptor that, with a cascade mechanism, activates downstream pathways such as RAS, PI3K/AKT, the STAT and NF-κB, involved in cell proliferation, differentiation, cell motility, invasion and survival. Furthermore, the stability and degradation of the MET receptor are regulated by the intracellular juxtamembrane domain, encoded by exon 14 of the gene, containing a tyrosine residue (Y1003). The phosphorylated Tyr1003 works as a binding site for the casitas-B-lineage lymphoma (CBL) E3 ubiquitin ligase that is able to ubiquitylate MET leading to internalization and degradation of the receptor. In NSCLC, point mutations of the MET gene can cause skipping of exon 14 during pre-mRNA splicing, leading to the loss of the CBL-binding site and increasing the half-life of the MET receptor. Increasing of MET gene copy numbers on chromosome 7 causes MET amplification while an upregulation of the MET protein receptor in the transcription phase leads to MET overexpression. Both these mechanisms can lead to a global increase in MET signaling. Finally, chromosomal translocation is responsible for the creation of a fusion gene with a wide variety of partners, such as TPR, KIF5B and HLA-DRB1, making the receptor constitutively activated. Abbreviations: AKT, protein kinase B; C- CBL, casitas-B-lineage lymphoma E3 ubiquitin; CDK, cyclin-dependent kinase; Cycl D1, cyclin D1; ERK, extracellular signal-regulated kinase; HGF, hepatocyte growth factor; KRAS, Kirsten rat sarcoma viral oncogene; MEK, mitogen-activated protein kinase; MET, mesenchymal epithelial transition; mTOR, mammalian target of rapamycin; NSCLC, non-small-cell lung cancer; NF-κB, nuclear factor κB; PARP, poly (ADP-ribose) polymerases; PI3K, phosphatidylinositol 3-kinase; RAF, rapidly accelerated fibrosarcoma; RhoA, ras homolog gene family, member A; STAT 3, signal transducer and activator of transcription 3
