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Title: Arkadia Family Ubiquitin-Ligases in TGFp Signalling
Author: Dixon, James Edward
ISNI:       0000 0001 3425 690X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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During vertebrate development and in human pathology the regulation of the level and duration of TGFp signalling is important in controlling cell plasticity, migration, proliferation and apoptosis. My work has focused on Arkadia (Akd) which is a nuclear RING-H2 domain E3 ubiquitin-ligase that enhances Smad2/3-mediated TGFp sign!llling and is essential in mammalian development. Akd has recently been shown to destroy inhibitory (I)-Smads, sensitising cells to TGFp ligands. Here I describe data that demonstrates a second more important mechanism by which Akd enhances and terminates Smad2/3 signalling in which phosphorylated(P)Smad2 and Smad3 are the targets for Akd. I have employed reporter' analyses to investigate the Akd protein domains required for ubiquitination, and highlight�· the requirement ofP-Smad2/3-interaction to activate Smad2/3-mediated signalling. This has lead to the hypothesis that the primary pathway of Akd is through ubiquitination of PSmad2/ 3s, which many co-operate with the function of Akd to destroy I-Smads. Furthermore, I have isolated a second Akd gene (Akd2) in mouse and human, and shown its function is complementary to enhance Smad2/3 signalling in reporter analyses. Moreover, I confirmed the importance of Akd in TGFp signalling by isolating a functional Akd homologue in the invertebrate drosophila melanogaster (termed dAkd). Akd and certain isoforms of Akd2 are ubiquitpusly expressed. I have employed reporter analyses to address the regulation of Akd genes post-transcriptionally and engineered tools to analyse these mechanisms in the�· embryo. My data strongly implicates post-translational regulation of Akd genes to fine-tune TGFp signalling in vivo. My study confirms the central role of the Akd family in regulation of TGFpsignals and highlights the importance of post-transcriptional control ofAkd genes. These data will be important in understanding how the alternate cellular interpretation of TGFp ligands is achieved in many important biological processes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available