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Title: Molecular analysis of the Drosophila JAK/STAT pathway receptor complex
Author: Stec, Wojciech
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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The JAK/STAT signalling pathway plays a central role in numerous biological processes contributing to development and maintenance of homeostasis. Drosophila melanogaster offers a conserved JAK/STAT pathway with much lower redundancy. For this reason, the fruit fly was used as a model organism to investigate genetic interactions and functions of the JAK/STAT pathway in the context of the whole organism. However, very little is known regarding the molecular mechanisms governing the Drosophila JAK/STAT pathway. Here, we present a molecular analysis of the sole receptor of the JAK/STAT pathway in Drosophila, Dome. We show that Dome shares characteristics with different sub-families of mammalian cytokine receptors. Specifically, the identified JAK binding site in Dome is reminiscent of that found in IFN? receptor, while constitutive endocytosis leading to lysosomal degradation shares similarities with the Leptin receptor. An increase in tyrosine phosphorylation and a shift in the ubiquitination pattern of the receptor in response to ligand binding are also described. Furthermore, the structure-function analysis of socs36E, the only SOCS-like protein in the Drosophila genome that can potently suppress the JAK/STAT pathway, revealed two independent mechanisms of action. Firstly, SOCS36E affects stability of the receptor, most likely by forming ubiquitin ligase via the SOCS box domian, a mechanism well described for all mammalian SOCS proteins. Secondly, regulation of Dome phosphorylation by the N-terminal domain of SOCS36E contributes to suppression of the JAK/STAT pathway in a SOCS box independent manner. Finally, two alleles of the Drosophila JAK that give rise to a phenotype reminiscent of human leukaemia, hopTuml and hopT42, are shown to increase transcriptional activity of the pathway reporter without increasing phosphorylation of STAT. Both mutations cause constitutive activation of the kinase independently of the receptor. Moreover, autophosphorylation kinetics of both mutants are unaltered, compared to the wild-type Hop, suggesting non-canonical signalling to be the underlying cause of oncogenicity.
Supervisor: Zeidler, Martin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available