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Title: Structural and functional analyses of H-Ras and R-Ras
Author: Love, Julie Ann
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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In this thesis I have sought to gain further insight into the regulation of integrin affinity and cellular function by Ras GTPases. A series of H- and R-Ras chimeras have been used to examine the hypothesis that specific sequences within these molecules govern their differential effects on integrin function and cellular transformation. Understanding the structure/function relationship between H-Ras and R-Ras may help to elucidate their downstream effectors which regulate integrin function and define the relevance of MAP kinase activation with regards to integrin activation and cellular transformation. This may lead to a better understanding of the development of cancer. Expression of the H- and R-Ras chimeras within an integrin reporter system (αβ-py cells) revealed that a C-terminal 25-amino acid stretch of H-Ras was required for full suppressive activity, and that the equivalent C-terminal 28-amino acid stretch of R-Ras was required to fully reverse H-Ras/Raf-intiated integrin suppression. The effects of these amino acids stretches on integrin function was further confirmed by investigations into the changes in cytoskeletal organisation and overall cellular morphology. Furthermore, the data suggest that the effects on integrin function are independent of the activation of the ERK1/2 MAP kinase pathway. This implicates a novel mechanism whereby Ras modulates integrin affinity. In summary, it is shown that H-Ras- and R-Ras-mediated integrin is regulated by distinct C-terminal domains. Moreover, integrin affinity modulation is independent of ERK1/2 MAP kinase activation. In addition there is an apparent correlation between suppression of integrin function and cellular transformation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available