Tyrosine phosphatase pez: a novel regulator of TGFβ signalling, epithelial-mesenchymal transition and protein secretion in development and cancer.
Date
2011
Authors
Belle, Leila
Editors
Advisors
Khew-Goodall, Yeesim
Journal Title
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Volume Title
Type:
Thesis
Citation
Statement of Responsibility
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Abstract
The body of work documented in this thesis defines the protein tyrosine phosphatase Pez as a novel positive regulator of TGFβ signalling, epithelialmesenchymal transition and protein secretion. In a zebrafish model of embryonic development, Pez was found to be expressed transiently in discrete, tissue-specific regions of the developing brain, heart, pharyngeal arches and somites, and knock-down of Pez expression was found to result in architectural defects in these organs, indicating a crucial role for Pez in organogenesis during embryonic development. Over-expression of Pez in epithelial MDCK cells induced an epithelial-mesenchymal transitio (EMT), as confirmed by increased expression of mesenchymal genes and EMT-associated transcription factors, concomitant with a reduction in epithelial gene expression and transition from epithelial to mesenchymal-like morphology. Pez-dependent induction of EMT was found to be a consequence of increased TGFβ signalling in Pez-expressing cells in this in vitro model. Furthermore, TGFβ₃ mRNA was found to be co-expressed with Pez in a number of tissues during zebrafish development, and TGFB₃ expression was lost from these tissues following Pez knock-down, suggesting that Pez is required for TGFB₃ expression in these tissues. Pez-dependent regulation of TGFβ was also found to occur in the setting of human breast cancers, with manipulation of Pez expression altering TGFB secretion in human breast cancer-derived cell lines. Additionally, altered Pez expression led to widespread changes in the secretome of these breast cancer cell lines. In breast and other epithelial cell types, Pez was found to localise predominantly to a perinuclear region that partially co-localised with markers of the golgi apparatus. Preliminary investigations suggest that Pez-dependent activation of golgi-localised Src family kinases may contribute to its effects in regulating protein secretion. Together, these results implicate Pez as a novel regulator of embryonic development, TGFβ production and EMT, and a modulator of the tumour cell secretome. Further investigation into the molecular mechanism by which Pez mediates these effects has the potential to enhance our understanding of essential biological processes contributing to embryonic development, tissue homeostasis, and human disease states, including cancer.
School/Discipline
School of Molecular and Biomedical Science
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2011
Provenance
Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.