Characterising the role of anterior gradient protein 2 in cell adhesion and metastasis

Clarke, Christopher Characterising the role of anterior gradient protein 2 in cell adhesion and metastasis. PhD thesis, University of Liverpool.

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Abstract

Anterior gradient protein 2 (AGR2) is overexpressed in many cancers, in particular those of the breast, ovary, prostate and pancreas. This overexpression tends to correlate with a poor disease prognosis for patients, probably as a result of increased incidence of metastases, and indeed, AGR2 has been shown to play a role in cell adhesion in different cell lines. Whilst AGR2 is a member of the protein disulphide isomerase (PDI) family of endoplasmic reticulum (ER) chaperones, there are also multiple reports of the secretion of AGR2 by cultured cells and the protein is also found in the serum and urine of cancer patients. AGR2 is a dimer, and the dimerisation interface is characterised here. A short, flexible region of the protein is also described, that seems to be involved in the regulation of the adhesion activity of AGR2. Through the use of stable cell lines expressing wild type and several mutant AGR2 proteins, it is shown here that wild-type AGR2 expression is associated with changes in cell adhesion and anchorage-independent cell growth, that are lost upon inhibition of protein dimerisation, mutation of the putative active site or a change in the sub-cellular localisation of the AGR2. Furthermore, the secretion of AGR2 has been confirmed through the discovery of a glycosylated, extracellular form of the protein. The expression of AGR2 is shown to be associated with a number of changes to the secreted proteome, with effects on both pro-adhesive and anti-adhesive proteins that may contribute to the role of AGR2 in cell adhesion. Overall, through combined biochemical, cell biology and mass spectrometry approaches, potential mechanisms whereby AGR2 might contribute to cell adhesion and metastasis are explored and discussed.

Item Type:	Thesis (PhD)
Additional Information:	Date: 2014-09 (completed)
Subjects:	?? Q1 ??
Depositing User:	Symplectic Admin
Date Deposited:	27 Aug 2015 10:49
Last Modified:	17 Dec 2022 01:06
DOI:	10.17638/02005402
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2005402