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Title: TROP2, a stem cell marker with oncogenic potential in prostate cancer : differential cleavage and regulation by PKC isoforms
Author: Wanger, Tim
ISNI:       0000 0004 5351 1541
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2014
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Trop2 is a type 1 transmembrane protein regulating proliferation, cell cycle progression, migration and anchorage independent growth (Cubas et al., 2009), which was identified as a cell surface marker on a subpopulation of prostate basal cells with stem cell characteristics (Goldstein et al. 2008). Trop2 undergoes regulated intramembrane proteolysis and cleavage induces self-renewal and proliferative activity of prostate cancer (PCa) stem cells (Stoyanova et al. 2013). This study aimed to investigate the regulation of Trop2 processing by Protein Kinase C (PKC) isoforms. PKCs represent a family of serine-threonine kinases which show altered activation or expression in various forms of cancer. PKCζ, an atypical PKC, is an important tumour suppressor and loss of function mutations in PCa have been identified, where it may regulate growth factor availability by proteolysis (Kim et al., 2013). My data showed that phorbol ester-induced activation of classical and novel PKCs resulted in ADAM17-mediated Trop2 cleavage and the release of full-length Trop2 containing ectosomes directly from the cell surface. In contrast, inhibition of atypical PKCζ caused internalization of Trop2 and its N-terminal cleavage in the endocytic compartment by ADAM10 and ADAM17, resulting in exosomal release of Trop2 fragments which remain connected via internal disulphide bridges. We described for the first time the existence of two pathways that lead to Trop2 processing at two distinct cleavage sites and that these cleavage events are differentially regulated by distinct PKC isoforms. We identified PKCζ as a novel major regulator of Trop2 function and showed that alternative Trop2 shedding occurs in PCa cells. This allows the examination of possible therapeutic intervention for PCa treatment, as well as investigations into whether heterogeneously released Trop2 ectodomains could be used as a novel marker in PCa diagnosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General)