A Direct Role for Met Endocytosis in Tumorigenesis

Nat Cell Biol. 2011 Jun 5;13(7):827-37. doi: 10.1038/ncb2257.

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.

MeSH terms

  • Animals
  • Cell Movement* / drug effects
  • Cell Proliferation
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Clathrin / metabolism
  • Dynamins / metabolism
  • Endocytosis* / drug effects
  • Endosomes / enzymology*
  • Enzyme Activation
  • Female
  • GRB2 Adaptor Protein / metabolism
  • Humans
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Mutation
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • RNA Interference
  • Receptors, Growth Factor / antagonists & inhibitors
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Soft Tissue Neoplasms / enzymology*
  • Soft Tissue Neoplasms / genetics
  • Soft Tissue Neoplasms / pathology
  • Soft Tissue Neoplasms / prevention & control
  • Stress Fibers / metabolism
  • Time Factors
  • Transfection
  • Tumor Burden
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Clathrin
  • GRB2 Adaptor Protein
  • Protein Kinase Inhibitors
  • Receptors, Growth Factor
  • Recombinant Fusion Proteins
  • Proto-Oncogene Proteins c-cbl
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • rac1 GTP-Binding Protein
  • Dynamins