Fig. 2

Pathways of c-Met signaling. a Overview of HGF/c-Met signaling via the canonical and non-canonical pathway. Canonical or “classical” HGF/Met signaling involves ligand-dependent and independent receptor activation which leads to the induction of downstream signaling cascades (left). Non-canonical HGF/c-Met signaling is independent of receptor activation. Generation of c-Met receptor fragments takes place under various cellular conditions such as apoptotic and necrotic stimuli as well as in the context of specific physiological circumstances. HGF is also able to exert signals independently of c-Met, e.g. upon interactions triggered by its heparin-binding domain. b Generation of c-Met fragments via shedding and cleavage by γ-secretase: Sheddases or metalloproteinases cleave full-length c-Met within its extracellular domain, resulting in different in a soluble extracellular N-terminal fragment (Met-NTF) and a membrane-associated C-terminal fragment (Met-CTF). Met-CTF can be further processed by the γ-secretase complex by presenilin-dependent intramembrane proteolysis (PS-RIP) into an intracellular domain (Met-ICD) which is routed to proteasomal degradation. Full-length membranous c-Met can also be internalized and cleaved by sheddases giving rise to Met-NTF and Met-CTF. These intracellularly generated c-Met fragments undergo lysosomal instead of proteasomal degradation. c Origin of c-Met fragments through intracellular cleavage by caspases and calpains: In response to apoptotic stimuli, c-Met is cleaved at two distinct sites in the intracellular domain by activated caspase-3, resulting in membrane-anchored p100 Met, a 40 kDa cytosolic p40 Met fragment and a small peptide (M10). Under necrotic conditions, c-Met is cleaved by metalloproteinases and further processed by calcium-independent proteases (calpains) instead of γ-secretase. The resulting product p40 Metcalpain differs from p40 Metcaspase by a few amino acid residues and is not able to promote apoptosis