Characterising the role of the AP3 complex in controlling integrin lysosomal delivery, cancer cell migration and growth


   School of Biosciences

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  Dr E Rainero, Dr A Peden  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Cell growth and migration are essential for a variety of physiological conditions, from development to immune responses, would healing and cancer. Understanding the molecular mechanisms controlling these is therefore essential to deepen our knowledge of how organisms develop and function. Cell-extracellular matrix (ECM) interaction is integral to both cell growth and migration and is mediated by the integrin family of plasma membrane receptors. Integrins are constantly internalised from and mainly recycled back to the plasma membrane. The way in which integrins are transported impacts on cell adhesion, proliferation and migration. Integrins bound to their ECM ligands are preferentially delivered to the lysosome. While the mechanisms controlling integrin endocytosis and recycling are well established, little is known about how lysosomal targeting is controlled. Interestingly, ligand-bound integrin lysosomal delivery is key to cell migration and growth. This project is built on our strong preliminary data showing that the Adaptor Protein complex 3 (AP3) is required for a2b1 integrin lysosomal delivery, which in turn promotes cancer cell migration and growth. Here, we will use a combination of approaches, including super-resolution microscopy, proximity proteomics and photo-activation to characterise the formation of the AP3/a2b1 complex on the early endosomal membrane and define the role of this complex in delivering ECM-bound a2b1 to the lysosome. Finally, we will use imaging approaches to investigate the role AP3/a2b1 complex and its regulator in controlling cancer cell migration and growth in complex 3D environments. In summary, this work will define the molecular mechanisms behind a basic biological process, how a2b1, a specific AP3 cargo, is sorted from EEs to lysosomes, which underpins cell migration and growth. Therefore, this knowledge will be instrumental for the development of therapies against diseases characterised by aberrant cell migration and growth, such as chronic wounds and cancer.

Biological Sciences (4)

Funding Notes

This position is for self funded or externally funded students only.

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: http://www.sheffield.ac.uk/postgraduate/research/apply/applying

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

https://rainerolab.wixsite.com/mysite

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