RTKs as Models for Trafficking Regulation: c-Met/HGF Receptor-c-Met Signalling in Cancer—Location Counts

c-Met, the receptor tyrosine kinase of Hepatocyte Growth Factor (HGF), plays a major role in tumour progression and constitutes an attractive target for cancer therapy. Upon ligand binding at the plasma membrane, c-Met triggers various signalling pathways, which promote cell responses such as proliferation, migration and survival. Recent studies have shown that HGF binding to c-Met also triggers a rapid endocytosis of c-Met, leading to its intracellular trafficking and ultimately degradation. However, c-Met remains bound to HGF and activated on endosomes and in fact its endocytosis is required for optimal signalling. Moreover c-Met exploits both its endocytosis and its subsequent intracellular trafficking to alter its signalling capacity. Finally, recent studies on oncogenic mutants of c-Met, reported in human cancers, have shown that activated c-Met accumulation on endosomes can lead to cell transformation. Here, we review the present knowledge about c-Met endocytosis and trafficking, the interplay between c-Met trafficking and signalling and the consequences on tumorigenesis. We discuss the idea that c-Met localisation, in addition to its activation, plays a key role in its signalling and possibly in cancer progression.