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, Gareth Howell, Jean-Marc Schwartz, Michael P. Smith () and Chiara Francavilla ()
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Joanne Watson: The University of Manchester
Harriet R. Ferguson: The University of Manchester
Rosie M. Brady: The University of Manchester
Jennifer Ferguson: The University of Manchester
Paul Fullwood: The University of Manchester
Hanyi Mo: The University of Manchester
Katherine H. Bexley: The University of Manchester
David Knight: The University of Manchester
Gareth Howell: The University of Manchester
Jean-Marc Schwartz: The University of Manchester
Michael P. Smith: The University of Manchester
Chiara Francavilla: The University of Manchester

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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 reveal FGFR signalling partners proximal to recycling endosomes by developing a Spatially Resolved Phosphoproteomics (SRP) approach based on APEX2-driven biotinylation followed by phosphorylated peptides enrichment. Combining this with traditional phosphoproteomics, bioinformatics, and targeted assays, we uncover that FGFR2b stimulated by its recycling ligand FGF10 activates mTOR-dependent signalling and ULK1 at the recycling endosomes, 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 cellular signalling.

Date: 2022
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DOI: 10.1038/s41467-022-34298-2

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