Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs
Authors
Smith, Michael PFerguson, Harriet R; orcid: 0000-0002-0283-4629
Ferguson, Jennifer
Zindy, Egor
Kowalczyk, Katarzyna M
Kedward, Thomas
Bates, Christian
Parsons, Joseph
Watson, Joanne
Chandler, Sarah; orcid: 0000-0003-3981-8590
Fullwood, Paul
Warwood, Stacey
Knight, David
Clarke, Robert B
Francavilla, Chiara; orcid: 0000-0003-1775-3386; email: chiara.francavilla@manchester.ac.uk
Publication Date
2021-06-04Submitted date
2020-10-29
Metadata
Show full item recordAbstract
Abstract: 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.Citation
The EMBO Journal, page e107182Type
articleDescription
From Wiley via Jisc Publications RouterHistory: received 2020-10-29, rev-recd 2021-04-27, accepted 2021-04-28, pub-electronic 2021-06-04
Article version: VoR
Publication status: Published
Funder: Wellcome Trust; Grant(s): 107636/Z/15/Z, 210002/Z/17/Z
Funder: UKRI | Biotechnology and Biological Sciences Research Council (BBSRC); Id: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/R015864/1, BB/M011208/1
Funder: UKRI | Medical Research Council (MRC); Id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/T016043/1
Funder: Cancer Research UK (CRUK); Id: http://dx.doi.org/10.13039/501100000289; Grant(s): A27445
Funder: NIHR Manchester Biomedical Research Centre; Grant(s): IS‐BRC‐1215‐20007
Funder: Breast Cancer Now; Grant(s): MAN‐Q2‐Y4/5