Notch is one of the major highly conserved signalling pathways that regulate cell-cell communication which involves gene regulation mechanisms that control multiple processes during development and adult life, including cell fate specification within progenitors.
Upon extracellular ligand binding, Notch transmembrane receptors are cleaved, releasing the intracellular domain (NICD) that translocates to the nucleus to regulate expression of specific developmental gene cohorts. NICD is highly labile, and phosphorylation-dependent turnover acts to restrict Notch signalling.
Most canonical Notch activity relies on this regulation of NICD turnover. Moreover, aberrant NICD turnover contributes to numerous cancers and diseases. Despite the multiple impacts of NICD turnover in both development and disease, the molecular mechanism regulating this turnover remains largely uncharacterised. The stability of NICD and therefore duration of the Notch signal is regulated by phosphorylation of the C-Terminal PEST domain which leads to subsequent recruitment of FBXW7, F-Box and WD Repeat Domain Containing 7, (a key component of the SCFSel10/FBXW7 E3 ubiquitin ligase complex). Ultimately, this leads NICD to ubiquitylation and proteasomal degradation. However, the molecular details of NICD degradation mediated by FBXW7 are not well understood.
We recently identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. We demonstrate both CDK1 and CDK2 can phosphorylate NICD in the domain where this crucial residue lies and that NICD levels vary in a cell cycle-dependent manner. Inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro in a number of human cell lines and in vivo during early vertebrate development in the presomitic mesoderm where Notch plays a critical role on the progressive formation of the segmented body axis.
This project will investigate whether this regulatory system is conserved in another in vivo context, namely in the Fruit fly Drosophila melanogaster where Notch was first identified in 1919. The lab of Dr.Jens Januschke has developed a novel tool with which to inhibit CDK1 function – through the generation of an analogue sensitive kinase.
1. Is Notch turnover sensitive to the CDK1 analogue sensitive kinase in Drosophila melanogaster embryonic development?
2. Is NICD turnover correlated with the cell cycle in Drosophila melanogaster embryonic development?
3. What is the functional consequence of interfering with Notch turnover during Drosophila melanogaster embryonic development?
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Life Sciences MSc by Research MSc by Research (Postgraduate) : Study : University of Dundee
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