Author: ["Carine Joffre","Rachel Barrow","Ludovic Ménard","Véronique Calleja","Ian R. Hart","Stéphanie Kermorgant"]
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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. Activating mutations in the receptor tyrosine kinase Met can promote tumorigenesis. These Met mutants are now shown to undergo altered endocytic trafficking, and the retention of active Met at endosomes correlates with increased tumour formation and metastasis.Cite this article
Joffre, C., Barrow, R., Ménard, L. et al. A direct role for Met endocytosis in tumorigenesis. Nat Cell Biol 13, 827–837 (2011). https://doi.org/10.1038/ncb2257 