Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs. (4th June 2021)

• Record Type: Journal Article
• Authors: Smith, Michael P; Ferguson, Harriet R; Ferguson, Jennifer; Zindy, Egor; Kowalczyk, Katarzyna M; Kedward, Thomas; Bates, Christian; Parsons, Joseph; Watson, Joanne; Chandler, Sarah; Fullwood, Paul; Warwood, Stacey; Knight, David; Clarke, Robert B; Francavilla, Chiara
• Is Part Of: EMBO journal. Volume 40:Number 14(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-06-04
• Subjects: fibroblast growth factor receptor -- quantitative phosphoproteomics -- receptor tyrosine kinases -- signalling -- trafficking; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020107182
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: How receptor tyrosine kinase signaling is integrated and fine‐tuned remains incompletely understood. Here, phosphoproteomics reveal reciprocal priming between FGRF and EGFR taking place at recycling endosomes in breast cancer cells. Phosphoproteomics approaches show that FGFR ligands inducing receptor recycling cause EGFR T693 phosphorylation at recycling endosomes. T693‐phosphorylated EGFR alters FGFR2b trafficking and signaling outcomes. FGFR2b primes EGFR to enhance EGF‐induced ERK stabilization and cell proliferation. Recycling endosomes act as signal integration hubs allowing the reciprocal priming between FGFR2b and EGFR. Abstract : Phosphoproteomics reveal that FGFR recycling ligands induce specific EGFR phosphorylation that in turn alters FGFR2b trafficking and signaling in breast cancer cells.