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dc.contributor.authorWalsh, Michael Hartley
dc.date.accessioned2015-09-28T14:28:09Z
dc.date.available2015-09-28T14:28:09Z
dc.date.issued2014-11
dc.identifier.citationWalsh, M.H. 2014. Phosphoproteomic Investigation of Differential Signalling Downstream of Class IA PI3K Isoforms. Queen Mary University of London.en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/8917
dc.descriptionPhDen_US
dc.description.abstractThe PI3K family is central to numerous cellular processes in both health and disease. The class IA isoforms of PI3K control such outputs as proliferation, metabolism and survival through their well-characterised function as lipid kinases, with their signalling thought to predominantly mediated by the Akt/PKB protein kinase. However there exist other signalling routes, including from the lipid kinase activity through other effectors, but also through a protein kinase function of the class IA isoforms themselves. Mass spectrometry is a powerful tool which has been central to the recent advances in phosphoproteomic techniques. It is now possible to use mass-spectrometry to probe the phosphoproteome of any number of systems in an unbiased and global manner. In this project, we aimed to advance our understanding of two aspects of class IA PI3K signalling which are relatively poorly understood. We used phosphoproteomic techniques which allowed us to provide answers to some old questions which have up to now proved elusive. First, we investigated the protein kinase activity of p110α. We used an in vitro protein kinase assay and coupled this to mass spectrometry techniques to identify direct substrates of p110α. We proposed two novel protein substrates and attempted to characterise them further, although we were hampered by lack of available biochemical tools. Second, we investigated the differential phosphoproteomes of the ubiquitously expressed class IA PI3K isoforms p110α and p110β in a panel of breast cancer cell lines. We used mass spectrometry-based phosphoproteomics and found significant differences in signalling between p110α and p110β in 4T1 cells, including differential regulation of previously described PI3K effectors, amongst them the Akt substrate PRAS40, and potential novel targets. Additionally, we found that some of these effects were conserved between cell lines.en_US
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council; AstraZenecaen_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectMedicineen_US
dc.subjectCell signallingen_US
dc.titlePhosphoproteomic Investigation of Differential Signalling Downstream of Class IA PI3K Isoforms.en_US
dc.typeThesisen_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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