Epithelial to mesenchymal transition (EMT) is a normal part of embryonic development, and contributes to carcinoma progression. During EMT, epithelial cells decrease cell-cell interactions and acquire an invasive phenotype. Epithelial cells interact with one another via several junctional complexes including the adherens junction and the desmosome. Changes in the adherens junction have been characterized during EMT, but desmosomes have received only limited attention. The goal of this dissertation is to ...
Epithelial to mesenchymal transition (EMT) is a normal part of embryonic development, and contributes to carcinoma progression. During EMT, epithelial cells decrease cell-cell interactions and acquire an invasive phenotype. Epithelial cells interact with one another via several junctional complexes including the adherens junction and the desmosome. Changes in the adherens junction have been characterized during EMT, but desmosomes have received only limited attention. The goal of this dissertation is to characterize the desmosome during TGF-beta induced EMT and to determine the mechanism(s), which contribute to desmosome disassembly. Characterization of desmosomes during TGF-beta induced EMT using immunofluorescence and western blot analysis showed that the desmosomal components decrease at the protein level by three days of TGF-beta treatment. Quantitative Real Time PCR showed that mRNA levels of the desmosomal components are not significantly decreased with TGF-beta treatment suggesting that the decrease is due to a posttranscriptional mechanism, and further studies showed TGF-beta treatment results in increased turnover of the desmosomal cadherins and the plakophilins. Studies done by other groups have shown that matrix metalloproteinases (MMPs) 2 and 9 are upregulated in MCF10A cells during TGF-beta treatment, and ADAM family members have also been shown to directly cleave the desmosomal cadherins. Thus, we asked whether metalloproteinase inhibitors could stabilize the desmosomal protein desmoplakin at cell-cell borders. Cells were treated with GM6001, a broad spectrum MMP inhibitor, or TAPI-0, an inhibitor of ADAM-17, with TGF-beta for three days, and immunofluorescence analysis showed that desmoplakin remained at cell-cell borders. These results suggest that metalloproteinase cleavage of the desmosome cadherins contributes to the disassembly of desmosomes during TGF-beta induced EMT. Increased turnover of plakophilin-3 during TGF-beta treatment was found to be due to calpain activity. Inhibitors of calpains stabilized plakophilin-3 during TGF-beta treatment, and it was found that the plakophilin-3 head domain was sensitive to calpains. However, plakophilin-2 is not degraded by calpains. These studies show that protease activity contributes to desmosome disassembly during TGF-beta induced EMT.
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