Spatially resolved phosphoproteomics reveals fibroblast growth factor receptor recycling-driven regulation of autophagy and survival

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 plas...

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Published in:	Nature communications Vol. 13; no. 1; p. 6589
Main Authors:	Watson, Joanne, Ferguson, Harriet R., Brady, Rosie M., Ferguson, Jennifer, Fullwood, Paul, Mo, Hanyi, Bexley, Katherine H., Knight, David, Howell, Gareth, Schwartz, Jean-Marc, Smith, Michael P., Francavilla, Chiara
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 03-11-2022 Nature Publishing Group Nature Portfolio
Subjects:	13 13/106 13/31 14/19 631/337/458/1733 631/45/475 631/80/313/1461 631/80/39 82/58 96/95 Autophagy Bioinformatics Biotinylation Cancer Cell fate Cell proliferation Cell survival Endocytosis Endocytosis - physiology Endosomes Endosomes - metabolism Fibroblast growth factor 10 Fibroblast Growth Factor 10 - metabolism Fibroblast growth factor receptors Fibroblasts Growth factors Homeostasis Humanities and Social Sciences Kinases Ligands Membranes multidisciplinary Peptides Protein turnover Protein-tyrosine kinase receptors Receptor, Fibroblast Growth Factor, Type 2 - metabolism Receptors Recruitment Science Science (multidisciplinary) Signaling Survival TOR protein Tyrosine
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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 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. Recruitment of Receptor Tyrosine Kinase signalling partners during endocytosis, specifically during recycling to the plasma membrane, is crucial to signal propagation and regulation. Here, the authors reveal FGFR signalling partners proximal to recycling endosomes with a spatially resolved phosphoproteomics approach.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-34298-2