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Reciprocal Priming between RTKs within Recycling Endosomes Orchestrates Cellular Signaling Outputs

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Abstract

Integration of signaling downstream from 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 still remain poorly elucidated. Focusing on distinct Fibroblast Growth Factor Receptors (FGFRs) we generated a detailed picture of recycling-dependent FGF signalling in breast cancer cells by combining quantitative phosphoproteomics and targeted assays. We discovered reciprocal priming between FGFRs and Epidermal Growth Factor Receptor (EGFR) within recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated cell cycle but not cell invasion. In turn, FGFR signaling primes EGF-mediated outputs. The discovery of reciprocal priming between distict families of RTKs within recycling endosomes will transform our understanding of signalling integration by pointing to recycling endosomes as crucial signalling hubs for orchestrating cellular behaviour. Therefore, targeting reciprocal priming rather than individual receptors may improve personalized therapies in breast and other cancers.

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... For example, an interaction between FGFR1 and EGFR can marginally increase epidermal growth factor (EGF)-mediated AKT and STAT3 signaling outputs in lung cancer cells [261]. Along this line, we have recently showed that FGFR2-IgIIIb and EGFR engage in reciprocal regulation of each other's signaling and trafficking in breast cancer cells [275], confirming that FGFR trafficking regulation may become a target for therapeutic intervention. ...
... As differential trafficking of FGFR drives intracellular signaling, we speculate that FGFR colocalization with noncanonical signaling partners, including EGFR, may contribute to novel FGFR oncogenic functions. For instance, FGF10/FGFR2-IgIIIb-dependent phosphorylation of EGFR on threonine (T) 693 in breast cancer cells and organoids regulates FGFR2-IgIIIb trafficking and signaling outputs, including cell proliferation [275]. This might have implications in TNBC, where both FGFRs and EGFR are highly expressed [337], and where this phosphorylated site may become a prognostic or predictive marker if a correlation between T693 phosphorylation, clinical parameters, and the response to combined EGFR/FGFR therapies are determined. ...
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