Insulin-like growth factor receptor activity in cancer biology & therapy responses

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dc.check.date10000-01-01
dc.check.embargoformatBoth hard copy thesis and e-thesisen
dc.check.entireThesisEntire Thesis Restricted
dc.check.infoIndefiniteen
dc.check.opt-outYesen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorO'Connor, Rosemaryen
dc.contributor.authorO'Shea, Sandra Patricia
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2016-09-06T10:47:43Z
dc.date.issued2016
dc.date.submitted2016
dc.description.abstractThe Insulin-like Growth Factor 1 Receptor (IGF-1R) has an essential function in normal cell growth and in cancer progression. However, anti-IGF-1R therapies have mostly been withdrawn from clinical trials owing to a lack of efficacy and predictive biomarkers. IGF-1R activity and signalling in cancer cells is regulated by its C-terminal tail, and in particular, by a motif that encompasses tyrosines 1250 and 1251 flanked by serines 1248 and 1252 (1248- SFYYS-1252). Mutation of Y1250/1251 greatly reduces IGF-1-promoted cell migration, interaction with the scaffolding protein RACK1 in the context Integrin signalling, and IGF- 1R kinase activity. Here we investigated the phosphorylation of the SFYYS motif and characterise the conditions under which this motif may be phosphorylated under. As phosphorylated residues, the SFYYS motif may also serve to recruit interacting proteins to the IGF-1R. To this end we identified a novel IGF-1R interacting partner which requires phosphorylated residues in the SFYYS motif to interact with the IGF-1R. This interaction was found to be IGF-1-dependent, and required the scaffold protein RACK1. The interaction of this binding protein with the IGF-1R likely functions to promote maximal phosphorylation of Shc and ERK in IGF-1-stimulated cell migration, and may be important for IGF-1 signalling in cancer cells. Lastly, we have investigated possible kinases that may confer resistance or sensitivity to the IGF-1R kinase inhibitor BMS-754807. In this screen we identified ATR as a mediator of resistance and showed that suppression or chemical inhibition of ATR synergised with BMS-754807 to reduce colony formation. This work has contributes to our understanding of IGF-1R kinase regulation and signalling and suggests that administration of anti-IGF-1R drugs with ATR inhibitors may have therapeutic benefit.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationO'Shea, S. P. 2016. Insulin-like growth factor receptor activity in cancer biology & therapy responses. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/3067
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2016, Sandra P. O'Shea.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectIGF-1Ren
dc.subjectATRen
dc.subjectBreast canceren
dc.subjectDNA damageen
dc.subjectPhosphorylationen
dc.thesis.opt-outtrue
dc.titleInsulin-like growth factor receptor activity in cancer biology & therapy responsesen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Science)en
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