Functional Regulation of the Discs Large Tumour Suppressor by Phosphorylation

Narayan, Nisha (2008). Functional Regulation of the Discs Large Tumour Suppressor by Phosphorylation. PhD thesis The Open University.



The human homologue of the Drosophila Discs Large Tumour suppressor, hDlg, has been subject to various speculations concerning its role in the cell, with studies indicating roles in establishing and maintaining cellular polarity, as well as in controlling cell proliferation. The biochemical mechanism by which it might act in executing either function, have however remained ambiguous. In this study we show that phosphorylation is a major post-translational modification of the protein, affecting both location and function. We show that hDlg is phosphorylated both by the MAPKs and the CDKs, and both groups of kinases affect different aspects of the protein's behaviour. Post osmotic shock, the phosphorylation of hDlg by JNK leads to its accumulation in vesicular structures which we identify as endosomes, while its phosphorylation by the p38 MAPK in addition to relocating it to sites of cell-cell contact, also makes it more susceptible to degradation by the HPV18 E6 oncoprotein. Secondly, we show that hDlg is differentially regulated during the cell cycle, with each stage of the cell cycle leading to a different localisation of the protein, including its accumulation at the mitotic spindle in the M phase, as well as at the midbody during cytokinesis. We show also that the protein is phosphorylated by the Cyclin Dependent Kinases (CDK) 1 and 2, in a cell-cycle dependent manner on two sites - serine 158 and serine 442, and that these phosphorylations render the protein more stable and less susceptible to ubiquitination. Finally we show that hDlg phosphorylated on serine 158 and on serine 442 is largely nuclear, and that both the HPV18 E6 and the HPV16 E6 oncoproteins, target this nuclear form for degradation. These findings help us understand the processes that regulate hDlg and how these modifications of the protein might contribute to its growth-regulatory function in the cell.

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