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Reciprocal Priming between Receptor Tyrosine Kinases at Recycling Endosomes Orchestrates Cellular Signalling Outputs

Michael P. Smith, Harriet R. Ferguson, Jennifer Ferguson, Egor Zindy, Katarzyna M. Kowalczyk, Thomas Kedward, Christian Bates, Joseph Parsons, Joanne Watson, Sarah Chandler, Paul Fullwood, Stacey Warwood, David Knight, Robert B. Clarke, Chiara Francavilla
doi: https://doi.org/10.1101/2021.01.04.425243
Michael P. Smith
1Division 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
1Division 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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Jennifer Ferguson
1Division 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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Egor Zindy
2Division of Cell Matrix and Regenerative Medicine, School of Biological Science, FBMH, The University of Manchester, M139PT, Manchester, UK
3Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), CPI 305/1, Rue Adrienne Bolland, 8, 6041 Gosselies, Belgium, Department of Biochemistry, University of Oxford, OX1 3QU, Oxford, UK
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Katarzyna M. Kowalczyk
1Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
3Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), CPI 305/1, Rue Adrienne Bolland, 8, 6041 Gosselies, Belgium, Department of Biochemistry, University of Oxford, OX1 3QU, Oxford, UK
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Thomas Kedward
4Division of Cancer Sciences, School of Medical Science, FBMH, The University of Manchester, M13 9PT, Manchester, UK
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Christian Bates
1Division 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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Joseph Parsons
4Division of Cancer Sciences, School of Medical Science, FBMH, The University of Manchester, M13 9PT, Manchester, UK
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Joanne Watson
5Division of Evolution and Genomic Sciences, School of Biological Science, FBMH, The University of Manchester, M139PT, Manchester, UK
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Sarah Chandler
1Division 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
1Division 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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Stacey Warwood
6Bio-MS Core Research Facility, FBMH, The University of Manchester, M139PT, Manchester, UK
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David Knight
6Bio-MS Core Research Facility, FBMH, The University of Manchester, M139PT, Manchester, UK
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Robert B. Clarke
4Division of Cancer Sciences, School of Medical Science, FBMH, The University of Manchester, M13 9PT, Manchester, UK
7Manchester Breast Centre, Manchester Cancer Research Centre
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Chiara Francavilla
1Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, M139PT, Manchester, UK
7Manchester Breast Centre, Manchester Cancer Research Centre
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  • For correspondence: chiara.francavilla@manchester.ac.uk
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SUMMARY

Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling-dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF-mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Clarification in the text and Supplemetary and EV Figures have been added.

Copyright 
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 June 14, 2021.
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Reciprocal Priming between Receptor Tyrosine Kinases at Recycling Endosomes Orchestrates Cellular Signalling Outputs
Michael P. Smith, Harriet R. Ferguson, Jennifer Ferguson, Egor Zindy, Katarzyna M. Kowalczyk, Thomas Kedward, Christian Bates, Joseph Parsons, Joanne Watson, Sarah Chandler, Paul Fullwood, Stacey Warwood, David Knight, Robert B. Clarke, Chiara Francavilla
bioRxiv 2021.01.04.425243; doi: https://doi.org/10.1101/2021.01.04.425243
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Reciprocal Priming between Receptor Tyrosine Kinases at Recycling Endosomes Orchestrates Cellular Signalling Outputs
Michael P. Smith, Harriet R. Ferguson, Jennifer Ferguson, Egor Zindy, Katarzyna M. Kowalczyk, Thomas Kedward, Christian Bates, Joseph Parsons, Joanne Watson, Sarah Chandler, Paul Fullwood, Stacey Warwood, David Knight, Robert B. Clarke, Chiara Francavilla
bioRxiv 2021.01.04.425243; doi: https://doi.org/10.1101/2021.01.04.425243

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