title: A direct role for Met endocytosis in tumorigenesis.
abstract: Compartmentalization of signals generated by receptor tyrosine kinase (RTK) endocytosis has emerged as a major determinant of various cell functions. Here, using tumour-associated Met-activating mutations, we demonstrate a direct link between endocytosis and tumorigenicity. Met mutants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes, activation of the GTPase Rac1, loss of actin stress fibres and increased levels of cell migration. Blocking endocytosis inhibited mutants' anchorage-independent growth, in vivo tumorigenesis and metastasis while maintaining their activation. One mutant resistant to inhibition by a Met-specific tyrosine kinase inhibitor was sensitive to endocytosis inhibition. Thus, oncogenicity of Met mutants results not only from activation but also from their altered endocytic trafficking, indicating that endosomal signalling may be a crucial mechanism regulating RTK-dependent tumorigenesis.
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Carine
authors.initials: C
authors.lastname: Joffre
authors.forename: Rachel
authors.initials: R
authors.lastname: Barrow
authors.forename: Ludovic
authors.initials: L
authors.lastname: Ménard
authors.forename: Véronique
authors.initials: V
authors.lastname: Calleja
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hart
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Kermorgant
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002966:Clathrin / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000201:enzymology*; D004789:Enzyme Activation; D005260:Female; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D022502:Stress Fibers / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002966:Clathrin; D051380:GRB2 Adaptor Protein; D047428:Protein Kinase Inhibitors; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D050721:Proto-Oncogene Proteins c-cbl; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020830:rac1 GTP-Binding Protein; D034281:Dynamins