Figure 1.

Activation, signalling, internalization and recycling of c-Met. (A) Representation of the activation of the c-Met heterodimer illustrating the catalytic and docking tyrosine residues in the non-phosphorylated inactive state, non-HGF-bound state (left) or the active state (right). HGF-mediated c-Met activation triggers the sequential trans-phosphorylation of catalytic tyrosines (Tyr1234-1235, red residues) and docking tyrosines (Tyr1349-1356, blue residues), determining the biochemical signature for the further recruitment of amplifier and transducer molecules. Grb2 and STAT3 directly associate with the c-Met carboxy-terminal tail, while Gab1 interacts both indirectly (through Grb2) or directly providing a docking structure for SHC, PI3K, SHP2, PLCγ1 and p120, resulting in activation of the downstream signalling pathways; (B) Representation of the internalization and recycling of c-Met. To prevent c-Met over-stimulation, several protein-tyrosine phosphatases downregulate the c-Met signal, reverting the catalytic and docking tyrosines to a non-phosphorylated inactive state. The dissociation of the intermediate molecules from the complex refines the tuning and timing of the c-Met-mediated biological response and allows further internalization of c-Met. The Cbl E3 ubiquitin ligase mediates ubiquitination of c-Met, providing a signal for c-Met internalization, which has been shown to be clathrin- or caveolin-dependent. Internalization can be enhanced by Grb2, CIN85, SNX2, CD44v6 and PTP1B. Once internalized, the c-Met receptor can be delivered to lysosomes to be degraded or it can be recycled back to the plasma membrane through the endosomal compartments. PKCε is important for the delivery towards the endosomes, from which the c-Met receptor can signal to specific signalling routes, including STAT3. Recycling back to the plasma membrane has been shown to be dependent on RCP, GGA3 and/or TSN4.