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


Project Description

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.

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.

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).

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Francavilla C. et al. (2013). Functional proteomics defines the molecular switch underlying FGF receptor trafficking and cellular outputs. Molecular cell 51, 707-722.

Mellman I. and Yarden Y. (2013). Endocytosis and cancer. Cold Spring Harbour perspectives in biology 5, a016949.

Sigismund S. et al. (2012) Endocytosis and signalling: cell logistics shape the eukaryotic cell plan. Physiological reviews 92, 273-366.

von Stechow L, Francavilla C, Olsen JV. (2015). Recent findings and technological advances in phosphoproteomics for cells and tissues. Expert Rev Proteomics 12(5):469-87.

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