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Signalling pathways downstream of cadherin

Hosking, CR; (2007) Signalling pathways downstream of cadherin. Doctoral thesis , UCL (University College London). Green open access

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Formation of cadherin-based adhesive structures at sites of cell-cell contact leads to activation of several signalling pathways inside the cell. In order to examine the molecular mechanisms involved in these pathways, my project focused on two binding partners of cadherin, pi20 catenin and Hakai. pi20 catenin (pi20) is an Armadillo family member, which binds to the cytoplasmic tail of cadherins at sites of cell-cell contact. It has been implicated in regulation of cell- cell adhesion by modulating cadherin trafficking, and also in the regulation of actin dynamics through its association with members of the Rho-GTPase family. The presence of pi20 in the nucleus observed for a number of cell lines indicates an additional nuclear function for this protein. A number of biochemical assays show that pi20 can bind to the transcription factor Glis2. In addition, pi20 expression can induce C-terminal cleavage of the Glis2 protein. This cleavage is increased by the overexpression of Src, suggesting a role for Src-mediated tyrosine phosphorylation of pi20. Since Glis2 has been shown to have a role in neuronal differentiation, an investigation was carried out on the effect of overexpressing Glis2 in the neural tube of developing chick embryos. Interestingly, overexpressing Glis2 inhibited neuronal differentiation. A similar effect was also observed when the cleaved form of Glis2 was co-expressed with pi20. These results suggest a nuclear role for pi20 by modulating the cleavage of the transcription factor Glis2, and potentially altering the transcription of genes in the neuronal differentiation pathway. Hakai is an E3 ubiquitin ligase for the E-cadherin complex, which competes for binding on the E-cadherin intracellular tail with pi20. As Hakai is ubiquitously expressed, it is likely that Hakai has other substrates in the cell. Using the results of a previously completed yeast two-hybrid screen, several potential binding partners for Hakai have been identified.

Type: Thesis (Doctoral)
Title: Signalling pathways downstream of cadherin
Identifier: PQ ETD:592911
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
URI: https://discovery.ucl.ac.uk/id/eprint/1445587
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