1. Figure 2 HGF/c-MET signalling pathway
components, interaction network, and mechanisms of negative regulation
Figure 2 | HGF/c-MET signalling pathway components, interaction network, and mechanisms of negative regulation. HGF induces dimerization and transautophosphorylation of c-MET, resulting in the recruitment of several Src homology 2 (SH2)-domain-containing signalling proteins, activation of downstream effector signalling, including the growth factor receptor-bound protein 2 (GRB2)–son of sevenless homologue 1 (SOS)–RAS–MAPK cascade, the PI3K/AKT axis, signal transducer and activator of transcription 3 (STAT3), SRC/FAK and rho-like GTPases such as ras-related C3 botulinum toxin substrate 1 (RAC1). Lateral cooperation with an interaction network, including the laminin receptor α6β4 integrin, the hyaluronan receptor CD44v6, and members of the semaphorin plexin B family, amplifies signal transduction, thereby sustaining c-MET signalling. The pathway can be negatively regulated by proteolytic cleavage by the a disintegrin and metalloproteinase (ADAM) family and γ-secretase, resulting in inhibition of c-MET signalling by soluble c-MET. c-MET can be internalized and degraded in lysosomes, or recycled to the cell surface. CBL, E3 ubiquitin-protein ligase CBL; EMT, epithelial-to-mesenchymal transition; NF-κB, nuclear factor-κB; PLC-γ, phospholipase Cγ; SHP2, tyrosine-protein phosphatase non-receptor type 11.
Bradley, C. A. et al. (2017) Targeting c‑MET in gastrointestinal tumours: rationale, opportunities and challenges
Nat. Rev. Clin. Oncol. doi: /nrclinonc