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Investigating the role of PTPN13 and ENTR1 in apoptotic cell death and proliferation

Carmona Serrano, Antonio (2019) Investigating the role of PTPN13 and ENTR1 in apoptotic cell death and proliferation. PhD thesis, University of Sheffield.

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Death receptor Fas/CD95 is a crucial component in the regulation of ligand induced apoptosis in many cell types. It is well known that several cancers exhibit a decreased cell surface expression of Fas and consequently escape the control of Fas-mediated apoptosis, although underlying mechanisms are unclear. PTPN13, a multi-PDZ domain phosphatase, directly interacts with Fas and low surface levels of Fas have been previously correlated with increased levels of PTPN13 in a wide variety of tumour cell lines. Here we report that ENTR-1, an established interacting partner of PTPN13, also regulates cell surface levels of Fas. ENTR-1 forms a novel endocytic complex with PTPN13 that controls Fas-mediated apoptotic signaling by regulating the delivery of internalized Fas receptors from the early endosomes to the endolysosomal degradation pathway. The complex mediates the endosome-to-lysosome sorting of Fas via Dysbindin-Hrs1 axis thereby controlling termination of Fas signal transduction. Taken together, our data provide novel insights into the molecular mechanism of Fas post­endocytic trafficking and signaling. As downregulation of any component of the complex increases Fas receptor levels at the cell surface and affects the sensitivity of the cells to Fas-mediated apoptosis, our findings open possible explanations on how cancer cells regulate cell surface levels of death receptors

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > Biomedical Science (Sheffield)
The University of Sheffield > Faculty of Science (Sheffield)
Depositing User: Mr Antonio Carmona Serrano
Date Deposited: 05 Aug 2019 08:17
Last Modified: 05 Aug 2019 08:17
URI: http://etheses.whiterose.ac.uk/id/eprint/24544

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