Regulation of intracellular trafficking of the insulin-like growth factor I receptor

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dc.check.date2028-09-30
dc.contributor.advisorO'Connor, Rosemary
dc.contributor.authorGodsmark, Granten
dc.contributor.funderScience Foundation Ireland
dc.contributor.funderSwiss Forum for International Agricultural Research
dc.date.accessioned2023-06-01T09:40:07Z
dc.date.available2023-06-01T09:40:07Z
dc.date.issued2023en
dc.date.submitted2023
dc.description.abstractInsulin-like Growth Factor 1 and its receptor (IGF-1R) are required for normal cellular growth, but aberrant expression is linked to the progression and development of many malignancies. Despite IGF-1R being a promising cancer therapeutic target, clinical targeting has not been generally successful. This has also highlighted gaps in our knowledge on IGF-1 signalling and how the IGF-1R and its regulatory regions function. Two tyrosine residues Tyr1250/1251 located within the 1248SFYYS1252 signalling motif of the IGF-1R are required for receptor internalisation, transformation and Golgi localisation. This thesis aimed to further investigate how this region and the C-terminal tail contribute to IGF-1R trafficking, sub-cellular localisation and regulation by using a range of cell lines and IGF-1R receptor mutants. Phosphorylation of Tyr1250/1251 was shown to be required for IGF-1R localisation to the Golgi and that a phosphomimetic EE (Y1250E/Y1251E) IGF-1R mutant is less stable, is more ubiquitinated and undergoes more rapid proteasomal degradation than wild type IGF-1R. Three lysine residues (Lys1256, Lys1294, Lys1324) were identified within the IGF-1R C-terminal tail as putative ubiquitin binding sites, but mutation of these to arginine in mutational studies established that all of these sites have a minor function in receptor ubiquitination. Peptides encompassing the hydrophobic Tyr1250/1251 site in the IGF-1R were recently proposed as a cargo-sorting motif that binds to the protein trafficking ESCPE-1 (SNX5/SNX6) complex, which rescues the IGF-1R from lysosomal degradation. This was tested this using full-length receptors expressed in different cell models and using siRNA-mediated suppression of SNX5/SNX6. However, our data did not replicate the published observations on SNX5/SNX6 knockout causing reduced IGF-1R protein expression. Furthermore, no effect of SNX5/SNX6 suppression on IGF-1R protein levels or location at different sub-cellular compartments including the Golgi was observed. Interestingly, SNX5/SNX6 suppression induced lysosomal accumulation at the leading edge of cells as well as decreased cellular migration. SNX5/SNX6 was observed to interact with the IGF-1R, but the hydrophilic Y1250E/Y1251E mutant exhibited a stronger interaction, than the hydrophobic Y1250F/Y1251F mutant, which suggest that this interaction may be modulated by phosphorylation in the full-length receptor. In summary, the findings confirm the importance of the IGF-1R C-terminal tail, in particular, Tyr1250/1251, in IGF-1R signalling and regulation. These tyrosines facilitate ubiquitin binding, SNX5/SNX6 interaction and Golgi localisation of the IGF-1R which all contribute to the transformed phenotype. Further research on the associated mechanisms should assist in tailoring future cancer therapy treatments to improve clinical efficacy.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGodsmark, G. K. 2023. Regulation of intracellular trafficking of the insulin-like growth factor I receptor. PhD Thesis, University College Cork.
dc.identifier.endpage202
dc.identifier.urihttps://hdl.handle.net/10468/14536
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2023, Grant Godsmark.
dc.rights.urihttps://creativecommons.org/publicdomain/zero/1.0/
dc.subjectIGF-1Ren
dc.subjectCanceren
dc.subjectGolgien
dc.subjectTraffickingen
dc.subjectReceptoren
dc.titleRegulation of intracellular trafficking of the insulin-like growth factor I receptor
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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