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Microtubule motors in cell migration and integrin trafficking


Project Description

Cell migration is vital for the development and health of multicellular organisms. However, enhanced cell migration is also a hallmark of cancer cells, and contributes greatly to metastasis. Understanding the mechanism and regulation of cell migration is therefore of key importance. For a cell to move forward, membrane components must be inserted into the leading edge of the cell to allow the plasma membrane (PM) to protrude. Integrins—transmembrane proteins that bind to the extracellular matrix outside the cell, and the actin meshwork inside the cell—allow the cell to form new connections with the substrate as the cell moves forward. A major source of membrane for forward movement comes from PM components that have been removed from the cell rear by endocytosis and are then recycled to the leading edge via the endocytic pathway. All steps of this recycling route involve transport of membranes along microtubules, with inward movement driven by dynein and outward movement driven by kinesin family members.
Although we have a basic understanding of the membrane trafficking steps required for cell migration, we know very little about which motors drive particular steps, and whether specific motor subtypes have distinct roles. We will disrupt microtubule motor function using a combination of depletion (using siRNA and CRISPR/Cas9) and overexpression or microinjection of function-blocking motor protein domains. We will determine the effects these treatments have on cell migration in 2D and 3D, analysing the speed of movement and the ability of the cell to migrate in a defined direction. We will assess the trafficking of specific integrins, and test whether the organisation of the recycling endocytic pathway is changed. By imaging the dynamics of the membranes containing integrins with high temporal and spatial resolution in migrating cells, we will define how this organelle motility contributes to cell migration.

Training/techniques to be provided:
Cell culture of human cell lines; transient transfection and generation of stable cell lines; molecular biology techniques; RNAi; immunofluorescence microscopy; live cell imaging (phase constrast, fluorescence); 3D cell migration assays.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a biological sciences subject. Candidates with experience in cell biology or with an interest in advanced light microscopy are encouraged to apply.

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

Flores-Rodriguez, N., Kenwright, D. A., Chung, P.-H., Harrison, A. W., Stefani, F., Waigh, T. A., Allan, V. J. and Woodman, P. G. (2015). ESCRT-0 marks an APPL1-independent transit route for EGFR between the cell surface and the EEA1-positive early endosome. J. Cell Sci. 128, 755-767
Ruane, P. T., Gumy, L. F., Bola, B., Anderson, B., Wozniak, M. J., Hoogenraad, C. C., & Allan, V. J. (2016). Tumour Suppressor Adenomatous Polyposis Coli (APC) localisation is regulated by both Kinesin-1 and Kinesin-2. Scientific Reports, 6, 27456
Wilson BJ, Allen JL, Caswell PT. (2018) Vesicle trafficking pathways that direct cell migration in 3D and in vivo. Traffic, 19:899-909
Caswell PT, Zech T. (2018) Actin-Based Cell Protrusion in a 3D Matrix. Trends Cell Biol. 2018, 28:823-834

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