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Characterization of TMEFF2; its role in tumour progression and development of targeting strategies for anti-cancer therapy

Gawel, Katarzyna 2013. Characterization of TMEFF2; its role in tumour progression and development of targeting strategies for anti-cancer therapy. PhD Thesis, Cardiff University.
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Abstract

TMEFF2 (transmembrane protein with EGF-like and two follistatin motifs 2) is a transmembrane protein expressed in brain and prostate and over-expressed in prostate cancer (Uchida et al. 1999; Horie et al. 2000). The role of TMEFF2 in prostate cancer is controversial. Several data indicate that TMEFF2 has cancer-promoting activity (Glynne- Jones et al. 2001; Ali and Knäuper 2007), while others suggest that TMEFF2 inhibits progression of cancer (Gery et al. 2002; Gery and Koeffler 2003). TMEFF2 is cleaved by membrane-anchored proteases, including disintegrin and metalloproteases (ADAMs) and -secretase (Ali and Knäuper 2007), but the biological meaning of TMEFF2 shedding is not known. It was hypothesized that the opposing findings describing the role of TMEFF2 in prostate cancer result from proteolytic processing of TMEFF2 by different proteases which are co-expressed with TMEFF2 in prostate cancer cells, such as the type II transmembrane serine proteases (TTSPs), prostasin and ADAMs. To support this hypothesis co-expression of TMEFF2 and serine proteases was analyzed in prostate cancer cell lines and clinical samples. The shedding of TMEFF2 by ADAMs and serine proteases was investigated using HEK293 cells expressing AP/V5 TMEFF2 or shedding resistant AP/V5 303-320TMEFF2 mutant (Ali and Knäuper 2007). The data obtained from AP activity assay and Western blot analysis of cell lysates showed that TMEFF2 is cleaved by serine proteases (matriptase and hepsin) and ADAMs (ADAM9, ADAM12). Moreover, serine proteases and ADAMs cleave TMEFF2 in different positions, generating several soluble TMEFF2 fragments. To establish the biological role of TMEFF2 processing, N-terminal TMEFF2 fragments predicted to be generated by TTSPs and ADAMs were expressed in E. coli and mammalian cells. Preliminary experiments using HEK293 and PNT2-C2 cells indicated that soluble TMEFF2 does not signal through ErbB receptors and suggested several signaling pathways that might be regulated by TMEFF2. The fate of TMEFF2 C-terminus following ectodomain shedding was examined by confocal microscopy and Western blotting, indicating that TMEFF2 cytoplasmic domain is likely degraded following the release of TMEFF2-ECD

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Dentistry
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: Prostate cancer; Ectodomain shedding; TMEFF2; ADAMs; Matriptase; Hepsin; Prostasin
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:27
URI: http://orca.cf.ac.uk/id/eprint/52861

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