Reciprocal Priming between RTKs within Recycling Endosomes Orchestrates Cellular Signaling Outputs

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.