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Spatially Resolved Phosphoproteomics Reveals Fibroblast Growth Factor Receptor Recycling-driven Regulation of Autophagy and Survival

Joanne Watson, Harriet R. Ferguson, Rosie M. Brady, Jennifer Ferguson, Paul Fullwood, Hanyi Mo, Katherine H. Bexley, David Knight, Jean-Marc Schwartz, Michael P. Smith, View ORCID ProfileChiara Francavilla
doi: https://doi.org/10.1101/2021.12.04.471203
Joanne Watson
1Division of Evolution, Infection and Genomics, School of Biological Science, FBMH, The University of Manchester, M139PT, Manchester, UK
2Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
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Harriet R. Ferguson
2Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
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Rosie M. Brady
3Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Man- chester, Manchester Cancer Research Centre, Wilmslow Rd, Manchester, M20 4GJ, UK
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Jennifer Ferguson
2Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
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Paul Fullwood
2Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
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Hanyi Mo
1Division of Evolution, Infection and Genomics, School of Biological Science, FBMH, The University of Manchester, M139PT, Manchester, UK
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Katherine H. Bexley
2Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
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David Knight
4Bio-MS Core Research Facility, FBMH, The University of Manchester, M139PT, Manchester, UK
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Jean-Marc Schwartz
1Division of Evolution, Infection and Genomics, School of Biological Science, FBMH, The University of Manchester, M139PT, Manchester, UK
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Michael P. Smith
2Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
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  • For correspondence: michael.smith-8@manchester.ac.uk chiara.francavilla@manchester.ac.uk
Chiara Francavilla
2Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
5Manchester Breast Centre, Manchester Cancer Research Centre, The University of Manchester, M139PT, Manchester, UK
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  • ORCID record for Chiara Francavilla
  • For correspondence: michael.smith-8@manchester.ac.uk chiara.francavilla@manchester.ac.uk
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Summary

Receptor Tyrosine Kinase (RTK) endocytosis-dependent signalling drives cell proliferation and motility during development and adult homeostasis, but is dysregulated in diseases, including cancer. The recruitment of RTK signalling partners during endocytosis, specifically during recycling to the plasma membrane, is still unknown. Focusing on Fibroblast Growth Factor Receptor 2b (FGFR2b) recycling, we revealed FGFR signalling partners proximal to recycling endosomes (REs) by developing a Spatially Resolved Phosphoproteomics (SRP) approach based on APEX2-driven biotinylation followed by phosphopeptide enrichment. Combining this with traditional phosphoproteomics, bioinformatics, and targeted assays, we uncovered that FGFR2b stimulated by its recycling ligand FGF10 activates mTOR-dependent signalling and ULK1 at the REs, leading to autophagy suppression and cell survival. This adds to the growing importance of RTK recycling in orchestrating cell fate and suggests a therapeutically targetable vulnerability in ligand-responsive cancer cells. Integrating SRP with other systems biology approaches provides a powerful tool to spatially resolve celllar signalling.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 04, 2021.
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Spatially Resolved Phosphoproteomics Reveals Fibroblast Growth Factor Receptor Recycling-driven Regulation of Autophagy and Survival
Joanne Watson, Harriet R. Ferguson, Rosie M. Brady, Jennifer Ferguson, Paul Fullwood, Hanyi Mo, Katherine H. Bexley, David Knight, Jean-Marc Schwartz, Michael P. Smith, Chiara Francavilla
bioRxiv 2021.12.04.471203; doi: https://doi.org/10.1101/2021.12.04.471203
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Spatially Resolved Phosphoproteomics Reveals Fibroblast Growth Factor Receptor Recycling-driven Regulation of Autophagy and Survival
Joanne Watson, Harriet R. Ferguson, Rosie M. Brady, Jennifer Ferguson, Paul Fullwood, Hanyi Mo, Katherine H. Bexley, David Knight, Jean-Marc Schwartz, Michael P. Smith, Chiara Francavilla
bioRxiv 2021.12.04.471203; doi: https://doi.org/10.1101/2021.12.04.471203

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