The four described proteolytic cleavages of the MET receptor. (A) Presenilin-regulated intramembrane proteolysis (PS-RIP) of MET, involving sequential cleavage by ADAM metalloproteases and γ-secretase under steady-state conditions. These cleavages generate the extracellular fragment, MET-NTF (also named soluble MET, sMET) and the intracellular fragments, p55 MET (MET-CTF) and p50 MET (MET-ICD), degraded respectively by the lysosome and proteasome. This proteolytic process is involved in receptor half-life regulation. (B) Caspase cleavages of MET during apoptosis at the juxtamembrane ESVD1000 site and the C-terminal DNADDEVD1380 site, generating p40 METcaspase. This fragment can promote mitochondrial permeabilization and amplifies cell death. (C) MET cleavages during calcium-stress-induced necrosis, involving the first proteolysis by PS-RIP and a second by calcium-regulated calpains at the T1036 site, generating the intracellular p40 METcalpain fragment. (D) Calpain cleavage of MET promoted by high cell density and the R970C MET mutation. The generated intracellular p45 MET fragment can promote epithelial cell migration and invasion.