Context Specificity in Causal Signaling Networks Revealed by Phosphoprotein Profiling

Summary Signaling networks downstream of receptor tyrosine kinases are among the most extensively studied biological networks, but new approaches are needed to elucidate causal relationships between network components and understand how such relationships are influenced by biological context and disease. Here, we investigate the context specificity of signaling networks within a causal conceptual framework using reverse-phase protein array time-course assays and network analysis approaches. We focus on a well-defined set of signaling proteins profiled under inhibition with five kinase inhibitors in 32 contexts: four breast cancer cell lines (MCF7, UACC812, BT20, and BT549) under eight stimulus conditions. The data, spanning multiple pathways and comprising ∼70,000 phosphoprotein and ∼260,000 protein measurements, provide a wealth of testable, context-specific hypotheses, several of which we experimentally validate. Furthermore, the data provide a unique resource for computational methods development, permitting empirical assessment of causal network learning in a complex, mammalian setting.
Graphical Abstract
Highlights Time-course assays of signaling proteins in cancer cell lines under kinase inhibition Causal conceptual framework for network analysis Data shed light on causal protein networks that are specific to biological context Resource for signaling biology and for benchmarking computational methods
Time-course assays under kinase inhibition are used to investigate protein signaling networks in cancer cell lines within a causal conceptual framework. This reveals that patterns of causal influence between signaling proteins depend on the biological context. The data provide a resource for signaling biology and computational methods development.