Met Receptor: A Moving Target

The activated hepatocyte growth factor (HGF) receptor (Met) undergoes rapid endocytosis and ubiquitin-dependent sorting to the lysosomal degradative pathway. New data suggest that this mode of down-regulation can be circumvented by mutant receptors bearing kinase-activating mutations that instead recycle to the plasma membrane. These mutant receptors can elicit enhanced signaling from endosomes, which is critical for cell motility and tumorigenesis. A proportion of HGF-activated wild-type receptors will also take the endosomal recycling route. This requires the recruitment of the adaptor protein GGA3, mediated through the interaction of GGA3 with the activated form of the small guanosine triphosphatase Arf6 and indirect binding to phosphorylated Met receptor through the adaptor protein Crk. This ability of receptors and effectors to be spatially controlled by the endosomal recycling pathway may play a prominent role in cellular functions such as motility.