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Syndecan-4 regulates cell migration during healing and cancer through caveolar endocytosis

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

Project Description

Cell migration during wound healing or cancer cell invasion involves responses to multiple factors including extracellular matrix and growth factors. Coordinated signalling by different classes of receptors determines whether cells migrate or not, and perhaps more importantly establish the polarity of the cell, and therefore the direction of travel. The simplest way to regulate receptors is to regulate surface availability. Likewise, the simplest way to localise receptor signalling within a cell is to regulate the distribution of the receptor itself. Therefore orchestrating receptor trafficking, and even more so, orchestrating trafficking in response to extracellular stimuli is a crucial mechanism that is only poorly understood. One molecule that has been shown to function synergistically with a range of receptors is the transmembrane proteoglycan, syndecan-4 (SDC4). SDC4 is known to regulate directional migration and knockout mouse studies have shown it to be essential for efficient wound healing, while epidemiological studies have linked it to cancer prognosis.

Preliminary data have revealed that SDC4 engagement triggers specific endocytic mechanisms, specifically caveolin-dependent endocytosis, meaning that it could regulate the surface expression and distribution of myriad receptors. The key questions now are how SDC4 triggers endocytosis, and how redistribution of specific receptors is achieved. This project will exploit existing, preliminary mass spectrometry data to investigate candidate molecules that will mediate the effects of SDC4-engagement on endocytosis. You will use RNAi and CRISPR technology to suppress expression of candidates in cell culture and monitor endocytosis initially using biochemical assays. Endocytosis of viable candidates in real time will then be investigated using high-resolution microscopy techniques in live samples. Through these experiments you will identify the key regulators and mediators of SDC4-dependent trafficking. The next step will use state-of-the-art phosphoproteomic techniques to identify SDC4-dependent phosphorylation events in the candidate regulators, before using site-directed mutagenesis to test the importance of phosphorylation in endocytosis. Through these experiments you will determine the mechanism and potentially identify ways to modify the trafficking of specific receptor cargoes.

A crucial component of the project will be to establish the functional impact of SDC4-dependent endocytosis. You will generate synthetic skin to model fibroblast migration during healing that could then be used the test the functional effect of your verified candidates. You will complement your migration studies by using atomic force microscopy to measure cell adherence to matrix components that affect the behaviour of cells both during healing and in cancer. Together, the functional studies will ensure that your detailed mechanistic findings have a relevance that can be applied to our ongoing development of healing therapies. During the PhD you will work alongside those developing therapies, so that you will gain experience in both mechanistic and translation cell biology.

Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.

Funding Notes

Entry requirements
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link: View Website

*All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information*.

References

Roper, Williamson, Bally, Cowell, Brooks, Stephens, Harrison, Bass. (2015) Ultrasonic stimulation of mouse skin reverses the healing delays in diabetes and aging by activation of Rac1. J Invest Dermatol. doi: 10.1038/jid.2015.224
http://www.ncbi.nlm.nih.gov/pubmed/26079528

Morgan, Hamidi, Bass, Warwood, Ballestrem, Humphries. (2013) Syndecan-4 phosphorylation is a control point for integrin recycling. Dev Cell. 24:472.
http://www.ncbi.nlm.nih.gov/pubmed/23453597

Steinberg, Heesom, Bass, Cullen. (2012) Sorting nexin-17 protects integrins from degradation by sorting between lysosomal and recycling pathways. J Cell Biol. 197(2): 219.
http://www.ncbi.nlm.nih.gov/pubmed/22492727

Bass, Williamson, Nunan, Humphries, Byron, Morgan, Martin, Humphries. (2011) A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis. Dev Cell. 21: 681.
http://www.ncbi.nlm.nih.gov/pubmed/21982645

https://www.sheffield.ac.uk/bms/research/bass

How good is research at University of Sheffield in Biological Sciences?

FTE Category A staff submitted: 44.90

Research output data provided by the Research Excellence Framework (REF)

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