A functional proteomic approach to reveal how receptor tyrosine kinases trafficking specifies cancer cell responses

Background and goals:

Cells respond appropriately to their surroundings by activating plasma membrane spanning receptors like Receptor Tyrosine Kinases (RTKs) and thereby adapting long-term outputs (e.g. proliferation, migration) to various extracellular signals. How the core signaling cascades are orchestrated by different RTKs to elicit distinct and specific cellular behaviours is still much debated. Endocytic trafficking of RTKs has been recently associated with signaling specificity. For instance, the escape of RTKs from canonical degradative routes to be recycled to the plasma membrane in response to certain growth factors affects downstream outputs. Imbalance in RTK trafficking contributes to several human diseases, including cancer.

The working hypothesis is that the signal controlling cancer cells proliferation versus cell migration is encoded by the trafficking route of RTKs in response to certain growth factors. Using a highly multidisciplinary approach this project aims at uncovering the key regulators of RTK trafficking and their influence on cancer cells signalling specificity and cellular decisions. The long-term aim is to identify trafficking-dependent signaling nodes that could be manipulated in vivo to re-direct cellular outputs.

Impact:

This project will exploit how functional proteomics enables advancements in cell biology (manipulation of trafficking-dependent outputs) and translational (understanding disease mechanisms) discoveries. Training will be provided in emerging disciplines (proteomics, bioinformatics, 3D cultures, imaging techniques).

This project will integrate:

- Cutting-edge Mass Spectrometry-based quantitative proteomics, interactomics and phosphoproteomics together with advanced methods in bioinformatics for a comprehensive analysis of trafficking-dependent signatures.

- Immunofluorescence-based and biochemical methods for validation of novel kinases and protein adaptors involved in RTKs degradation and recycling.

- Functional assays (cell proliferation, migration, etc) in 2D and 3D culture of cancer cells to uncover the role of kinases and adaptors in long-term responses.

- Drug-based perturbation of kinases and RTKs to re-direct cancer cell responses.

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. Candidates with previous laboratory experience, particularly in cell culture and molecular biology, are particularly encouraged to apply.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Genetics

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.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”

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