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Title: The role of the deubiquitinating enzyme USP17 in endocytosis and the regulation of Ras converting enzyme 1 activity
Author: Jaworski, Jakub
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2013
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Ubiquitination and deubiquitination are protein posttranslational modifications that are used in distinct ways to regulate a myriad of cellular activities. Previously, Ubiquitin Specific Protease 17 (USP17) has been shown to be required for cell cycle progression and cell motility. The research presented in this thesis gives further insights into the roles of this deubiquitinating enzyme. The data presented in this thesis reveals that USP17, shown before to hav~ a negative impact on RCE1 activity, in fact regulates the localization and stability of a novel isoform of RCE1. This mammalian specific isoform is required, in addition to the widely recognised RCE1 protein, for proper processing and plasma membrane localization of oncogenic CaaX box GTPase H-Ras. This isoform undergoes K63-type polyubiquitination, which controls its subcellular localization and can be deubiquitinated by USP17, which in turn leads to isoform's destabilization. This represents a novel mechanism of ubiquitination-dependent regulation of RCE1 and explains the critical role of USP17 in cellular processes involving GTPase function such as cell growth and migration. The data presented in this thesis also uncovers a requirement of USP17 for clathrin mediated endocytosis (CM E) of transferrin receptor, an archetypical substrate for this internalization route, and epidermal growth factor receptor (EGFR). In the cells with silenced expression of USP17 a number of core components of the clathrin coated pit, the assembly of which is of key importance in CME, appear to be mislocalized. Further investigation demonstrates that USP17 expression is required for re-localization of phosphatidylinositol-4-phosphate 5-kinase (PIP5K~) to the plasma membrane and localized phosphatidylinositol (4,5)-biphosphate (PIP 2) production, something that plays an indispensable role in the recruitment of the various adaptors and accessory proteins required for CME. Collectively, these data demonstrate that USP17 controls RCE1 activity, through deubiquititation of a novel RCEl isoform, and that its expression is required for CME. These observations may not only be significant to understanding how RCE1 and USP17 function, but may also aid in future drug discovery efforts to target either USP17 or RCE1.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available