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dc.contributor.authorBarrow, Rachel Jenny Mary; N.B EMBARGOED UNTIL 2015-01-01
dc.description.abstractMet, the receptor of Hepatocyte Growth Factor, is a receptor tyrosine kinase (RTK) overexpressed or mutated in cancer. RTKs have been increasingly recognised to signal post-endocytosis, possibly leading to unique consequences on cellular outcome due to the spatial and temporal activation of downstream signalling pathways. The objectives of my study were to investigate the role of Met “endosomal signalling” in cancer progression. I found, using four human breast cell lines, that the requirement of Met endocytosis for Met signalling as well as Met trafficking significantly vary with the cells’ aggressiveness, suggesting Met resides longer on endosomes in invasive cells. Furthermore Met endosomal localisation increases with the progression of breast cancer of human samples. Our study suggests that the endosomal location of Met is important in breast cancer progression. I used a model of Wt and two Met oncogenic mutants, M1268T and D1246N, expressed in NIH3T3 fibroblasts. I determined some mechanisms regulating the constitutive endocytosis and defect in degradation of the mutants. I established that targeting these mechanisms could be used to reduce Met mutants’ tumourigenicity. Thus impairing c-Cbl or Grb2 expression and/or binding to Met mutant or restoring Met mutant degradation through inhibiting the chaperone protein HSP90, greatly reduced the transforming capacities of the mutants in vitro and in vivo, including the D1246N that I show to be resistant to small molecule Met inhibitors.en_US
dc.publisherQueen Mary University of London
dc.titleSpatial signalling of Met in canceren_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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    Theses Awarded by Queen Mary University of London

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