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Title: Spatial signalling of Met in cancer
Author: Barrow, Rachel Jenny Mary
ISNI:       0000 0004 2734 3433
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2012
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Met, 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine