Met receptor dynamics and signalling.

The receptor for hepatocyte growth factor (HGF), Met, controls a programme of invasive growth that combines proliferation with various moto- and morphogenetic processes. This process is important for development and organ regeneration, but dysregulation in transformed tissues can contribute to cancer progression and metastasis. Acute stimulation of tissue culture cells with HGF leads to Met downregulation via degradation through an endocytic mechanism that also requires proteasome activity. Perturbation of Met trafficking on the endocytic pathway, either at the level of the internalisation step or during sorting at the early endosome, leads to altered signalling outputs. Ubiquitination of Met through the E3-ligase Cbl is required for receptor downregulation, and a mutant receptor defective in Cbl binding is able to transform cells. We discuss the hypothesis that some naturally occurring Met mutants implicated in cancer may transform cells owing to defects in their trafficking along the endosomal degradation pathway.