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(BBSRC DTP) Mapping Notch endocytic signalling pathways via quantitative proteomics in Drosophila melanogaster

Project Description

Extracellular signalling allows cells to communicate with one another in the context of tissues and influence the fate of their neighbouring cells, transducing signals from the external environment to the nucleus to affect the expression of target genes. Such processes are critically active during development and cell differentiation. One of the key players in this process is the ubiquitous signalling receptor Notch, which underpins many physiological processes in the cell. Proteolytic cleavage of the protein at the cell membrane leads to release of its intracellular domain which can find its way to the nucleus via several signalling routes, often involving membrane-bound vesicles called endosomes (1). These endosomal signalling routes can occur in both a Clathrin-dependent and independent “basal” manner, with differential processing in the two routes leading to activation/suppression of different sets of genes. Exactly how the various Notch interacting partners influence it during these endosomal signalling pathways is, however, not known. Using Drosophila S2 cells as a model system, we have carried out two genome wide RNAi screens representing the two routes, to determine a high-quality set of Notch interactors that influence Notch expression, and wish to integrate this data with wider bioinformatics data to better understand how the signalling networks are constituted. We will then carry out a comprehensive global quantitative proteomics experiment to determine how the two different signalling pathways affect the proteome, and defining downstream Notch targets that are differentially expressed. This will reinforce hypotheses generated by the bioinformatics network analyses, which we will subsequently validate using a combination of targeted proteomics experiments using bespoke protein standards (2), and attendant cell biology and biochemistry (1). We also aim to examine the knockdown effects on the most informative and potent Notch interactors in vivo. Our overall aim is therefore to characterise the different regulatory mechanisms promoted by the two Notch signalling routes, defining attendant changes in the target genes at the protein level, and placing this into a phenotypic context for Drosophila embryogenesis and development.

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.


1. Shimizu H, Woodcock SA, Wilkin MB, Trubenová B, Monk NA, Baron M. Compensatory flux changes within an endocytic trafficking network maintain thermal robustness of Notch signaling. Cell. 2014 May 22;157(5):1160-74. doi: 10.1016/j.cell.2014.03.050. PubMed PMID: 24855951.
2. Lawless C, Holman SW, Brownridge P, Lanthaler K, Harman VM, Watkins R, Hammond DE, Miller RL, Sims PF, Grant CM, Eyers CE, Beynon RJ, Hubbard SJ. Direct and Absolute Quantification of over 1800 Yeast Proteins via Selected Reaction Monitoring. Mol Cell Proteomics. 2016 Apr;15(4):1309-22. doi:10.1074/mcp.M115.054288. PubMed PMID: 26750110;

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