Figure 2.

MET signaling pathway. After MET activation, PI3K can bind either to MET directly or indirectly with GAB1 and signals through the AKT/protein kinase B axis. AKT can inactivate the pro-apoptotic protein BCL-2 antagonist of cell death (BAD) and activate the E3 ubiquitin-protein ligase MDM2, which results in apoptosis suppression and cell survival promotion. Moreover, AKT can also activate mammalian target of rapamycin (mTOR), which stimulates protein synthesis and cell growth. MET activation also signals through the RAS-MAPK pathway. The nucleotide exchanger protein Son of Sevenless (SOS) activates RAS by binding with SHC and GRB2 (GRB2-SOS complex). This leads to activation of the v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which subsequently stimulates the MAPK effector kinase (MEK) and results in MAPK activation. MAPK phosphorylates ERK, which is the final effector of the cascade. The RAS-MAPK pathway is responsible for cell proliferation, cell motility and cell cycle progression. A third major downstream axis of MET signaling is the Signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 can bind to MET directly resulting in STAT3 phosphorylation, which regulates cell transformation, tubulogenesis and invasion. Finally, the fourth major cascade of MET activation is through the IκBα-NF-κB complex. NF-κB is bound to IκBα forming an inactive form. The phosphorylation of either PI3K-AKT or SRC activates IκB kinase (IKK) and results in degradation of IκBs. NF-κB is then released and translocated to the nucleus to stimulate gene transcription.