Regulation of insulin-like growth factor receptor activity and its therapeutic targeting in cancer

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dc.contributor.advisor O'Connor, Rosemary en
dc.contributor.author Rieger, Leonie
dc.date.accessioned 2020-09-01T13:17:36Z
dc.date.available 2020-09-01T13:17:36Z
dc.date.issued 2020-04-08
dc.date.submitted 2020-04-08
dc.identifier.citation Rieger, L. 2020. Regulation of insulin-like growth factor receptor activity and its therapeutic targeting in cancer. PhD Thesis, University College Cork. en
dc.identifier.endpage 298 en
dc.identifier.uri http://hdl.handle.net/10468/10440
dc.description.abstract Insulin-like Growth Factor-1 Receptor signalling is essential for cell growth, and also promotes migration, survival and cellular transformation, thus, linking it to cancer progression. IGF-1R activity and signalling in cancer cells is regulated by the C terminal tail of the receptor. In particular the Tyr1250/1251, as their mutation to phenylalanine (FF) profoundly impairs IGF-1 signalling and the crosstalk between Integrin and IGF 1R signalling that facilitates a migratory phenotype in cancer cells. This thesis investigated the mechanisms of adhesion-modulated IGF-1R signalling, the function of Tyr1250/1251, and whether these mechanisms might influence the efficacy of IGF-1R-targeted drugs. Following the identification of FER kinase as a mediator of sensitivity to IGF 1R kinase inhibition, we found that ectopic expression of FER enhanced IGF-1R and SHC/MAPK pathway activation in an IGF-1R kinase independent manner. FER also specifically phosphorylated the IGF-1R on Tyr1250/1251. FER activity was cell adhesion-dependent and FER expression correlated with a migratory cancer phenotype. FER inhibition profoundly decreased IGF-1R and SHC signalling and reduced cell migration in breast cancer cells. The mechanisms and consequences of IGF-1R phosphorylation on Tyr1250/1251 phosphorylation were investigated for their contribution to IGF-1R function. It was established that IGF-1R, FER and FAK kinase activity may all contribute to Tyr1250/1251 phosphorylation and that cell adhesion is required for this phosphorylation. The consequence of Tyr1250/1251 phosphorylation was further investigated using a phosphomimetic Y1250E/Y1251E (EE) and the non-phosphorylatable FF IGF-1R mutant. These studies determined that IGF 1R phosphorylation on Tyr1250/1251 IGF-1R enhanced IGF-1R internalisation and proteasomal degradation. Moreover, the WT and EE receptors became rapidly internalised in response to IGF-1 ligation and accumulated in the Golgi apparatus, while the FF mutant remained at the plasma membrane or sites of cell adhesion. Importantly, Golgi associated IGF 1R signalling correlated with a migratory cancer cell phenotype, and disruption of the Golgi apparatus impaired IGF-1-promoted SHC phosphorylation and cell migration. In migratory cells, the formation of new focal adhesion points caused a transient release of the IGF-1R from the Golgi-apparatus to the membrane and lower IGF-1R Tyr1250/1251 phosphorylation. Thus, phosphorylation on Tyr1250/1251 enables IGF-1R signalling from the Golgi apparatus, and Golgi-derived IGF-1R signalling can support an aggressive cancer phenotype. Overall, this study identifies FER kinase and Tyr1250/1251 phosphorylation as adhesion-dependent mechanisms that modulate IGF-1R signalling and localisation in migratory cancer cells. The fact that the IGF-1R may be activated by other kinases and is predominantly located in the Golgi in migratory cells may explain the poor clinical efficacy of monoclonal antibodies and kinase inhibitors that specifically target the surface IGF-1R. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2020, Leonie Rieger. en
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Cancer en
dc.subject Tyrosine phosphorylation en
dc.subject IGF-1R internalisation and trafficking en
dc.subject Adhesion-modulated IGF-1R signalling en
dc.title Regulation of insulin-like growth factor receptor activity and its therapeutic targeting in cancer en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD - Doctor of Philosophy en
dc.internal.availability Full text not available en
dc.description.version Accepted Version en
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en
dc.internal.school Biochemistry and Cell Biology en
dc.internal.conferring Autumn 2020 en
dc.internal.ricu Cancer Biology at UCC en
dc.availability.bitstream embargoed
dc.check.date 2025-06-24


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© 2020, Leonie Rieger. Except where otherwise noted, this item's license is described as © 2020, Leonie Rieger.
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