The c-MET oncoprotein: Function,mechanisms of degradation and its targeting by novel anti-cancer agents

BackgroundThe c-MET oncoprotein drives cancer progression in a variety of tumors through its signaling transduction pathways. This oncoprotein is also degraded by multiple mechanisms involving the lysosome, proteasome and cleavage by proteases. Targeting c-MET degradation pathways may result in effective therapeutic strategies.Scope of reviewSince the discovery of oncogenic functions of c-MET, there has been a great deal of effort to develop anti-cancer drugs targeting this oncoprotein. Unexpectedly, novel di-2-pyridylketone thiosemicarbazones that demonstrate marked anti-tumor activity, down-regulate c-MET through their ability to bind intracellular iron and via mechanisms including, down-regulation of MET mRNA, enhanced lysosomal processing and increased metalloprotease-mediated cleavage.Major conclusionsThe c-MET oncoprotein regulation and degradation pathways are complex. However, with increasing understanding of its degradation mechanisms, there is also greater opportunities to therapeutically target these pathways.General significanceUnderstanding the mechanisms of degradation of c-MET protein and its regulation could lead to novel therapeutics.