Regulation of intestinal epithelial homeostasis by the desmosomal cadherins Público
Kolegraff, Keli (2011)
Published
Abstract
Regulation of intestinal epithelial homeostasis by the
desmosomal cadherins
By Keli Nicole Kolegraff
Desmocollin-2 (Dsc2) and desmoglein-2 (Dsg2) are the transmembrane
cell adhesion proteins of desmosomes. Down-regulation of Dsc2 has
been reported in colorectal carcinomas, however no mechanistic
studies have examined the contribution of Dsc2-deficiency to
tumorigenesis. Using RNAi to down-regulate the expression of Dsc2,
I have examined the effect of Dsc2 loss on the behavior of colonic
epithelial cells. Down-regulation of Dsc2 in a model colonic
epithelial cell line SK-CO15 increases cell proliferation and
enhances β-catenin signaling, a well-established
pro-proliferative pathway in intestinal epithelial cells.
Furthermore, Dsc2-deficient cells exhibit activation of Akt, a
serine/threonine kinase which has been reported to regulate the
transcriptional activity of β-catenin. Inhibition of Akt with
triciribine or siRNA-mediated Akt depletion prevents the activation
of β-catenin-dependent transcription and cell proliferation
following Dsc2 loss. These data suggest that decreased expression
of Dsc2 promotes cell proliferation via activation of
Akt/β-catenin signaling. Given that aberrant activation of
β-catenin signaling plays an important role in the progression
of colorectal carcinomas, I also examined the ability of
Dsc2-deficient cells to grow as tumors in immunodeficient mice.
Notably, the parental cell line SK-CO15 is non-tumorigenic and does
not form tumors in mice, however, down-regulation of Dsc2 enables
tumor formation in vivo. Furthermore, inhibition of Akt
strongly attenuates the growth of Dsc2-deficient cells. Taken
together, this work defines a novel link between the desmosomal
cadherins, Akt, and β-catenin and provides mechanistic
evidence that loss of Dsc2 may contribute to the progression of
epithelial cancers.
Table of Contents
Table of Contents
Chapter 1: Introduction. 1
The Origin and Molecular Basis of Intercellular Adhesion.
2
1.1.1 How do cells adhere to one another? 2
1.1.2 To each (tissue), his own (cadherin). 3
1.1.3 Differential expression of cadherin family members mediates
cell-type specific sorting. 4
1.1.4 E-cadherin is required for epithelial cell polarity.
4
1.1.5 Cadherin engagement promotes cell differentiation and altered
expression of cadherins perturbs tissue homeostasis. 4
1.2 Intercellular Adhesive Junctions Confer Functional
Properties to Tissues. 5
1.2.1 Tight junctions regulate tissue permeability and barrier
function. 5
1.2.2 Desmosomes reinforce intercellular adhesive contacts and
enable tissues to resist mechanical stress. 7
1.3 Intercellular Adhesive Junctions in the Context of Disease:
Chronic Inflammation of the Intestine. 12
1.4 Hypothesis: Altered Expression of the Desmosomal Cadherins
Affects Intestinal Epithelia Homeostasis.
14
1.5 References. 16
1.6 Figures and Legends. 21
Chapter 2: Loss of desmocollin-2 confers a tumorigenic phenotype
to colonic epithelial cells through activation of
Akt/β-catenin signaling. 24
2.1 Abstract. 26
2.2 Introduction. 27
2.3 Results. 30
2.4 Discussion. 38
2.5 Materials and Methods. 46
2.6 References. 52
2.7 Figure Legends. 58
2.8 Figures. 64
2.9 Supplementary Data. 70
Chapter 3: Characterization of full-length and proteolytic
cleavage fragments of desmoglein-2 in native human colon and
colonic epithelial cell lines. 77
3.1 Abstract. 78
3.2 Introduction. 79
3.3 Results. 81
3.4 Discussion. 85
3.5 Materials and Methods. 89
3.6 References. 92
3.7 Figure Legends. 94
3.8 Figures and Supplementary Data. 98
Chapter 4: Conclusions and Future Directions.
105
4.1 The Desmosomal Cadherins. 105
4.2 Loss of Desmocollin-2 Promotes Tumorigenesis.
106
4.3 Desmosomal Cadherins and the Regulation of Lipid Raft
Signaling Pathways. 106
4.4 Evidence of Distinct Signaling Functions for the "Partner"
Desmosomal Cadherins Desmocollin-2 and Desmoglein-2.
107
4.5 Controlling Desmoglein-2 Function by Proteolysis.
108
4.6 What is the Significance of Altered Desmoglein-2 Expression
in Chronic Intestinal Inflammation? 109
4.7 In Summary. 110
4.8 References. 112
Appendix: Cellular Domains Chapter 19 - The Tight Junction and
Desmosomes. 114
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