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Understanding how the tumor cell markers epidermal growth factor receptor (EGFR) and Src are downregulated

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

Project Description

EGFR and other ErbB family members are receptor tyrosine kinases (RTKs) that initiate numerous cellular responses, including differentiation, growth, survival and migration. Their overexpression or mutation is often associated with tumorigenesis. Src is major determinant of tumour formation, and is overexpressed or hyperactivated frequently in tumours. The actions of Src and EGFR are inter-dependent; EGFR activates Src, and active Src (pY416-Src) in turn phosphorylates EGFR on specific residues. This feedback generates proliferative signalling pathways. Hence, defective control of EGFR-Src leads to transformation, and understanding how activated EGFR-Src complexes are downregulated is of critical medical importance.

The downregulation pathway followed by activated EGFR is well documented. Activated EGFR is internalised from the cell surface, and is then ubiquitinated at the early endosome. Ubiquitinated receptor is sorted at the endosome to a trafficking pathway that leads ultimately to the lysosome, ensuring efficient degradation and hence downregulation of the receptor. Any receptor that escapes ubiquitination is recycled back to the cell surface, where it can continue to signal. Many of the cellular components that participate in EGFR downregulation are known. In contrast, the downregulation of activated Src is poorly understood. Key questions are how Src itself is trafficked, and whether the presence of activated Src influences the efficiency of EGFR degradation versus recycling.

This project will use a combination of cell biological and biochemical approaches to investigate how Src-EGFR complexes are trafficked within the endosomal pathway, and to understand how the activity of each of these important tyrosine kinases contributes to trafficking decisions. The findings will be of general significance in helping us to understand why the combination of hyperactivated EGFR and Src kinases can be so damaging, and may contribute to the design of novel clinical interventions.

Techniques: the student will learn mammalian cell culture and transfection methods, immunofluorescence microscopy and live cell imaging, protein biochemistry.


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

• Citri & Yarden. Nat. Rev. Mol. Cell Biol. 7, 505–516 (2006)
• Kim et al. Nat Rev Clin Onc 6,587–595 (2009)
• Sorkin & Goh Exp Cell Res 315, 683–696 (2009)
• Doyotte et al PNAS 105, 6308–6313 (2008).
• Stefani et al. Curr. Biol. 21, 1245–1250 (2011)

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