Trafficking and signalling of oncogenic met
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The Receptor Tyrosine Kinase (RTK) Met influences behaviour of several
cancers by controlling growth, survival and metastasis. Recently,
compartmentalisation of signals generated by RTKs, due to their
endocytosis / trafficking, has emerged as a major determinant of various
cell functions. The aim of my project was to study oncogenic Met signalling
in relation to endosomal trafficking and to determine the consequences of
such spatial changes on tumour cell growth and migration in vitro and in
vivo.
The model studied was NIH3T3 cells stably transfected with Wild type (Wt)
Met or with three distinct mutants reported in human cancers. I found that
two activating mutations in the kinase domain are highly tumorigenic in
vivo. Using functional assays and tumour growth experiments, I
demonstrated that one mutant is highly sensitive to Met specific tyrosine
kinase inhibitors (TKI) while another is resistant. Such results suggested
that therapeutical approaches to these mutants should be different.
Furthermore, I demonstrated a direct link between endocytosis and
tumorigenicity, suggesting a major role for Met endosomal signalling in
cancer progression. Using confocal microscopy and quantitative
biochemical assays, I demonstrated that Met mutants displayed an
increased endocytosis and recycling and a decreased degradation profile.
This led to an accumulation of phosphorylated Met on endosomes that
induced activation of the GTPase Rac1, loss of stress fibres and increased
cell migration. Blocking endocytosis by pharmacological and genetic
4
means inhibited mutants’ anchorage independent growth and, strikingly,
tumorigenesis and experimental metastasis. Interestingly, the mutant
resistant to TKI inhibition was sensitive to endocytosis inhibition. Taken
together, these results suggest that Met localisation constitutes a major
determinant in neoplastic development, while Met activation alone is
insufficient to effect this change.
Authors
Joffre, CarineCollections
- Theses [3709]