Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. John Di Guglielmo

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.

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