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Regulation of Notch receptor signalling in development and cancer

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

The control of cell differentiation during development requires communication between cells via diffusible growth factors and cell-cell adhesion mediated signalling molecules. The Notch receptor is an example of the latter class and regulates the timing and outcome of cell differentiation decisions in many different tissues during development and the regulation of stem cells. The Notch signal must be precisely regulated to prevent inappropriate signalling since misactivation of Notch can cause cancer. Notch was first identified in Drosophila but has subsequently been identified in a range of vertebrate species, including four versions of the gene in humans. The activity of Notch in vivo has to be precisely controlled spatially and temporally. Using the Drosophila model system, our group has identified novel mechanisms of Notch signal regulation, which involve directing Notch to different locations in the endocytic trafficking pathway, depending on the activity of different ubiquitin ligase proteins. We are using genetic, biochemical and cell biological analyses to investigate the regulation of Notch endosomal sorting and activity and the role this regulation plays in determining correct development and in avoiding cancer.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

• Baron M. (2012) Endocytic routes to Notch activation. Semin Cell Dev Biol. 23:437-42.
• Djiane A. Shimizu H, Wilkin M, Mazleyrat S, Jennings, M, Avis J, Bray, S, Baron M. (2011) Su(dx) E3-Ubiquitin ligase dependent and independent functions of Polychaetoid, the Drosophila ZO-1 homologue J. Cell Biol. 192:189-200.
• Wilkin M, Tongngok P, Gensch N, Clemence S, Motoki M, Yamada K, Hori K, Franklin E, Taniguchi-Kanai M, Matsuno K, Baron M. (2008) Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway. Dev Cell 15:762-72.
• Cordle J, Johnson S, Tay JZY, Roversi P, Wilkin M, Hernandez B, Shimizu H, Jensen S, Whiteman P, Boquan J, Redfield C, Baron, M, Lea SM, Handford PA. (2008) A conserved face of the Jagged/Serrate DSL Domain is involved in Notch Trans-Activation and Cis-Inhibition. Nat Struct Mol Biol: 15:849-57.
• Wilkin MB, Carbery AM, Fostier M, Aslam H, Mazaleyrat SL, Higgs J, Myat A, Evans DA, Cornell M, Baron M. (2004) Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Current Biology 14:2237-2244.

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