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Preparing the acid bath: how epidermal growth factor receptor (EGFR) controls its own down-regulation


Project Description

Signalling by cell surface receptors determines nearly every aspect of the cell’s response to its environment. Endosomes are hubs for regulating these signalling pathways: signalling is maintained if internalised, activated receptors remain resident in the endosome or are recycled to the cell surface, but is down-regulated if receptors are targeted for degradation by being sorted via the multivesicular body (MVB) to the lysosome. Differential endocytic sorting exerts a decisive influence on the lifetime of activated receptors such as epidermal growth factor receptor (EGFR), and consequently on the duration of signalling and the pattern of downstream responses.
Critically, sorting of EGFR to the degradative pathway is accompanied by acidification of the endosome/MVB, which promotes endosomal maturation and the exposure of EGFR to active lysosomal hydrolases. Based on recent published phosphoproteomics data, we believe that activated EGFR promotes endosome acidification by regulating a family of membrane proteins that couple the endosomal proton pump to membrane trafficking. We will test whether this is the case, as part of a broad examination of how signalling determines how EGFR negotiates the endocytic pathway. Specifically, Interferon induced transmembrane proteins (IFITMs) are tyrosine phosphorylated in response to EGF stimulation, raising the possibility that IFITMs are signalling targets that control the endosomal trafficking of EGFR.
In other contexts, IFITMs are essential for the acidification and maturation of endosomes carrying pathogenic bacteria, raising the possibility that regulation of IFITMs controls transit of EGFR through acidifying endocytic compartments, towards lysosomal degradation. This novel hypothesis merits further investigation. The overall objective of the PhD will be to establish how IFITMs couple endosomal acidification to other aspects of transport through endosomes towards the lysosome.
Aims:
1. Verify how members of the IFITM family are phosphorylated downstream of EGFR.
2. Dissect the role of IFITMs in EGFR transit through the endocytic pathway.

Training/techniques to be provided:
The project will use a wide range of cell biology skills to manipulate protein function and to test effects on EGFR trafficking and cell fate. Techniques will include: cell culture, transfection, RNAi, CRISPR, fluorescence microscopy, biochemistry (e.g. immunoblotting, phospho-peptide analysis), mass spectrometry.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy 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.

References

[1] Mellman I and Yarden Y. Cold Spring Harbor Perspectives in Bioogyl 5, a016949, (2013).
[2] Francavilla C et al. Nature Structural and Molecular Biology 23, 608-618, (2016).
[3] Woodman P and Tabernero L Biochem. Soc. Trans. 46, 1037-1046 (2018).

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