Galectin-3 and Annexin A2 regulate the stability of cell surface proteins to control epithelial barrier function. Open Access

Rankin, Carl (2014)

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The gastrointestinal epithelium functions as an important barrier that separates luminal contents from underlying tissue compartments thereby maintaining mucosal homeostasis. Mucosal wounds in inflammatory disorders compromise the critical epithelial barrier. In response to injury, intestinal epithelial cells (IECs) remodel cell matrix adhesions and intercellular junctions as they proliferate and migrate to cover denuded surfaces. AnnexinA2 (AnxA2) and Desmoglein-2 (Dsg2) proteins have been reported to regulate wound closure and epithelial barrier function. In Chapter 2 I identify a mechanism by which AnxA2 controls IEC migration and wound closure. These studies revealed that AnxA2 controls IEC migration by regulating endocytosis of β1 integrin and turnover of cell-matrix adhesions. In Chapter 3 I identify the association of a glycan binding protein, Galectin-3, with an intercellular junction protein, Dsg2, in intestinal epithelial cells. Galectin-3 stabilizes Dsg2 at the cell surface thereby influencing intercellular adhesion and intestinal epithelial barrier function.

Table of Contents

Chapter 1: Molecular mechanisms of intestinal epithelial barrier regulation and repair. 1

1.1 Organization and function of the intestinal epithelium. 2

1.2 Intestinal epithelial wound closure. 2

1.3 Annexin A2. 3

1.4 Intestinal epithelial cell migration. 3

1.5 Intestinal epithelial intercellular adhesion and desmosomes. 5

1.6 Galectin-3. 7

Chapter 2: Annexin A2 regulates β1 integrin internalization and intestinal epithelial cell migration. 21

2.1 Introduction. 22

2.2 Materials and methods. 24

2.3 Results. 27

2.3.1 AnxA2 promotes epithelial cell migration and wound closure

2.3.2 Down-regulation of AnxA2 increases cell-matrix adhesion

2.3.3 Cell surface β1 integrin stability is increased in cells with down- regulated AnxA2

2.3.4 AnxA2 promotes β1 integrin localization in endosomes

2.3.5 β1 integrin internalization is delayed in IECs with down-regulated AnxA2

2.4 Discussion. 33

Chapter 3: Galectin-3 regulates desmoglein-2 and intestinal epithelial intercellular adhesion. 53

3.1 Introduction. 54

3.2 Materials and methods.56

3.3 Results. 60

3.3.1 Gal3 associates with Dsg2 in a glycosylation dependent manner

3.3.2 Intercellular adhesion is controlled by Gal3

3.3.3 Dsg2 protein stability is influenced by Gal3

3.3.4 Inhibition of Gal3 in vivo decreases intestinal epithelial Dsg2 protein

3.4 Discussion. 63

Chapter 4: Summary and future directions. 77

4.1 Summary - AnxA2 regulation of endocytosis. 78

4.2 Future directions - AnxA2 regulation of endocytosis. 79

4.3 Summary - Gal-3 regulation of Dsg2. 81

4.4 Future directions - Gal-3 mediated stabilization of Dsg2. 82

References. 88

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