{"id":{"repo_id":"uwo","oai_identifier":"oai:uwo.scholaris.ca:20.500.14721/37042"},"canonical_url":"https://search.dev.ndltd.org/etd/uwo/oai:uwo.scholaris.ca:20.500.14721/37042","repository":{"repo_id":"uwo","name":"Western University","base_url":"https://uwo.scholaris.ca/server/oai/request"},"display":{"title":"The Effects of Atypical Protein Kinase C on TGFβ Signalling","abstract":"The transforming growth factor beta (TGFβ) signalling pathway is an essential regulator of many cellular processes including epithelial growth control, epithelial to mesenchymal transition (EMT), apoptosis, and the establishment of developmental fate. Alterations in TGFβ signalling patterns are associated with various pathological disorders such as fibrosis and cancer. In recent years it has become clear that regulation of TGFβ signalling is dependent on the trafficking and endocytosis of the TGFβ receptors, however, the factors that control these processes are still under investigation. In this thesis, I examined the role of Protein Kinase C (PKC) in the regulation of TGFβ signalling pathways and found that the Atypical PKC isoforms (aPKC; a subgroup of the PKC family) indeed can alter TGFβ receptor signaling. My work has shown that the modulation of aPKC expression or activity using inhibitors and/or small interfering RNA (siRNA) prolongs the temporal phosphorylation of the downstream transcription factor Smad2 through altered receptor membrane trafficking. Furthermore, I showed that aPKC activity and expression alters the phosphorylation and degradation of Par6, which in turn affects TGFβ induced EMT and migration. Finally, I examined global gene expression changes in aPKC silenced cells - and related these effects to altered Smad nuclear accumulation. Notably, we also found that these cells demonstrate enhanced p38 MAPK signalling, which sensitizes them to TGFβ induced apoptotic response. In conclusion, I found that aPKC isoform activity and expression is intricately linked to the regulation of various TGFβ receptor signalling pathways that control gene expression, EMT, and apoptosis.","abstract_html":"The transforming growth factor beta (TGFβ) signalling pathway is an essential regulator of many cellular processes including epithelial growth control, epithelial to mesenchymal transition (EMT), apoptosis, and the establishment of developmental fate. Alterations in TGFβ signalling patterns are associated with various pathological disorders such as fibrosis and cancer. In recent years it has become clear that regulation of TGFβ signalling is dependent on the trafficking and endocytosis of the TGFβ receptors, however, the factors that control these processes are still under investigation. In this thesis, I examined the role of Protein Kinase C (PKC) in the regulation of TGFβ signalling pathways and found that the Atypical PKC isoforms (aPKC; a subgroup of the PKC family) indeed can alter TGFβ receptor signaling. My work has shown that the modulation of aPKC expression or activity using inhibitors and/or small interfering RNA (siRNA) prolongs the temporal phosphorylation of the downstream transcription factor Smad2 through altered receptor membrane trafficking. Furthermore, I showed that aPKC activity and expression alters the phosphorylation and degradation of Par6, which in turn affects TGFβ induced EMT and migration. Finally, I examined global gene expression changes in aPKC silenced cells - and related these effects to altered Smad nuclear accumulation. Notably, we also found that these cells demonstrate enhanced p38 MAPK signalling, which sensitizes them to TGFβ induced apoptotic response. In conclusion, I found that aPKC isoform activity and expression is intricately linked to the regulation of various TGFβ receptor signalling pathways that control gene expression, EMT, and apoptosis.","abstract_has_math":false,"creators":["Gunaratne, Adrian D"],"institution":"The University of Western Ontario","degree_name":"Ph D","degree_level":null,"degree_discipline":"Pharmacology and Toxicology","degree_department":null,"school":null,"contributors":[],"advisors":["John Di Guglielmo"],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-03-24","date_published":"2014-03-24","updated_at":"2026-07-27T21:55:54Z","subjects":["Transforming growth factor beta (TGFβ)","Protein Kinase C (PKC)","Epithelial to mesenchymal transition (EMT)","Par6","Smad Signalling","p38 MAPK"],"languages":["en_ca"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/20.500.14721/37042","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["John Di Guglielmo"]},{"key":"dc:creator","label":"Author","values":["Gunaratne, Adrian D"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-07-10T21:28:58Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2025-07-10T21:28:58Z"]},{"key":"dc:date.issued","label":"Date","values":["2014-03-24"]},{"key":"dc:publisher","label":"Institution","values":["The University of Western Ontario"]},{"key":"dc:type","label":"Dc Type","values":["thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmacology and Toxicology"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph D"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Transforming growth factor beta (TGFβ)","Protein Kinase C (PKC)","Epithelial to mesenchymal transition (EMT)","Par6","Smad Signalling","p38 MAPK"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_ca"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/20.500.14721/37042"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The thesis cover page in the PDF document includes references to Western University’s previous institutional repository platform, known as Scholarship@Western, and links to that platform (beginning with ir.lib.uwo.ca). In citing or referring to this thesis, use the DOI or handle from this page instead. Sample citation: Author name, \"Thesis title.\" (Year). Western University Open Repository. https://doi.org/10.71858/123456."]},{"key":"dc:description.abstract","label":"Abstract","values":["The transforming growth factor beta (TGFβ) signalling pathway is an essential regulator of many cellular processes including epithelial growth control, epithelial to mesenchymal transition (EMT), apoptosis, and the establishment of developmental fate. Alterations in TGFβ signalling patterns are associated with various pathological disorders such as fibrosis and cancer. In recent years it has become clear that regulation of TGFβ signalling is dependent on the trafficking and endocytosis of the TGFβ receptors, however, the factors that control these processes are still under investigation. In this thesis, I examined the role of Protein Kinase C (PKC) in the regulation of TGFβ signalling pathways and found that the Atypical PKC isoforms (aPKC; a subgroup of the PKC family) indeed can alter TGFβ receptor signaling. My work has shown that the modulation of aPKC expression or activity using inhibitors and/or small interfering RNA (siRNA) prolongs the temporal phosphorylation of the downstream transcription factor Smad2 through altered receptor membrane trafficking. Furthermore, I showed that aPKC activity and expression alters the phosphorylation and degradation of Par6, which in turn affects TGFβ induced EMT and migration. Finally, I examined global gene expression changes in aPKC silenced cells - and related these effects to altered Smad nuclear accumulation. Notably, we also found that these cells demonstrate enhanced p38 MAPK signalling, which sensitizes them to TGFβ induced apoptotic response. In conclusion, I found that aPKC isoform activity and expression is intricately linked to the regulation of various TGFβ receptor signalling pathways that control gene expression, EMT, and apoptosis."]},{"key":"dc:title","label":"Title","values":["The Effects of Atypical Protein Kinase C on TGFβ Signalling"]}]}],"canonical_facts":{"dc:contributor.advisor":["John Di Guglielmo"],"dc:creator":["Gunaratne, Adrian D"],"dc:date.accessioned":["2025-07-10T21:28:58Z"],"dc:date.available":["2025-07-10T21:28:58Z"],"dc:date.issued":["2014-03-24"],"dc:description":["The thesis cover page in the PDF document includes references to Western University’s previous institutional repository platform, known as Scholarship@Western, and links to that platform (beginning with ir.lib.uwo.ca). In citing or referring to this thesis, use the DOI or handle from this page instead. Sample citation: Author name, \"Thesis title.\" (Year). Western University Open Repository. https://doi.org/10.71858/123456."],"dc:description.abstract":["The transforming growth factor beta (TGFβ) signalling pathway is an essential regulator of many cellular processes including epithelial growth control, epithelial to mesenchymal transition (EMT), apoptosis, and the establishment of developmental fate. Alterations in TGFβ signalling patterns are associated with various pathological disorders such as fibrosis and cancer. In recent years it has become clear that regulation of TGFβ signalling is dependent on the trafficking and endocytosis of the TGFβ receptors, however, the factors that control these processes are still under investigation. In this thesis, I examined the role of Protein Kinase C (PKC) in the regulation of TGFβ signalling pathways and found that the Atypical PKC isoforms (aPKC; a subgroup of the PKC family) indeed can alter TGFβ receptor signaling. My work has shown that the modulation of aPKC expression or activity using inhibitors and/or small interfering RNA (siRNA) prolongs the temporal phosphorylation of the downstream transcription factor Smad2 through altered receptor membrane trafficking. Furthermore, I showed that aPKC activity and expression alters the phosphorylation and degradation of Par6, which in turn affects TGFβ induced EMT and migration. Finally, I examined global gene expression changes in aPKC silenced cells - and related these effects to altered Smad nuclear accumulation. Notably, we also found that these cells demonstrate enhanced p38 MAPK signalling, which sensitizes them to TGFβ induced apoptotic response. In conclusion, I found that aPKC isoform activity and expression is intricately linked to the regulation of various TGFβ receptor signalling pathways that control gene expression, EMT, and apoptosis."],"dc:identifier.uri":["https://hdl.handle.net/20.500.14721/37042"],"dc:language.iso":["en_ca"],"dc:publisher":["The University of Western Ontario"],"dc:subject":["Transforming growth factor beta (TGFβ)","Protein Kinase C (PKC)","Epithelial to mesenchymal transition (EMT)","Par6","Smad Signalling","p38 MAPK"],"dc:title":["The Effects of Atypical Protein Kinase C on TGFβ Signalling"],"dc:type":["thesis"],"thesis:degree_discipline":["Pharmacology and Toxicology"],"thesis:degree_name":["Ph D"]},"updated_at":"2026-07-27T21:55:54Z"}