biostudies-literatureUnknown17(1)Garrido-Rodriguez MSignaling pathways are useful models for interpreting molecular data, but their coverage has long been constrained by classic biochemistry methods. The growing corpus of kinase-substrate interactions, coupled to phosphoproteomics improvements, pave the way to revisit classic signaling pathways. In this study, we explore context-specific signaling pathway inference from phosphoproteomics and kinase-substrate networks. Focusing on epidermal growth factor (EGF), we conduct a meta-analysis and generate three datasets representing the most comprehensive characterization of the EGF response to date. We infer kinase-kinase pathways and compare them to different ground truth sets. Literature-curated networks consistently yield the highest recovery of ground-truth interactions, with modest gains frNature communications2071https://www.ebi.ac.uk/biostudies/studies/S-EPMC12949236biostudies-literatureBenchmarking EGF signaling pathway inference using phosphoproteomics and kinase-substrate interactions.PMC12949236Potel CGarrido-Rodriguez MBecher ISavitski MMSaez-Rodriguez JRodriguez-Mier PBurtscher MLMuller-Dott SfalseBenchmarking EGF signaling pathway inference using phosphoproteomics and kinase-substrate interactions.Signaling pathways are useful models for interpreting molecular data, but their coverage has long been constrained by classic biochemistry methods. The growing corpus of kinase-substrate interactions, coupled to phosphoproteomics improvements, pave the way to revisit classic signaling pathways. In this study, we explore context-specific signaling pathway inference from phosphoproteomics and kinase-substrate networks. Focusing on epidermal growth factor (EGF), we conduct a meta-analysis and generate three datasets representing the most comprehensive characterization of the EGF response to date. We infer kinase-kinase pathways and compare them to different ground truth sets. Literature-curated networks consistently yield the highest recovery of ground-truth interactions, with modest gains fr2026-01-01T00:00:00Z2026 Feb2026-07-16T23:25:40.786Z2026-07-12T03:11:21.577ZS-EPMC129492364174143010.1038/s41467-026-69332-0