Significance A key challenge in understanding cell communication is to characterize the coordinated activity of signaling pathways. A number of studies suggest that signaling pathways can regulate each other by direct control of ligand and receptor expression levels, triggering sequential signaling events in cells. To address the extent of sequential signaling, we profiled the transcriptional responses of ligand and receptor genes to single and combinatorial signaling pathway inductions in cell lines. Our analysis revealed that transcriptional regulation of genes encoding pathway components is a major level of signaling cross-talk, especially in the context of costimulation of signaling pathways.