Combinatorial expression motifs in signaling pathways

Cell-cell signaling pathways comprise sets of variant receptors that are expressed in different combinations in different cell types. This architecture allows one pathway to be used in a variety of configurations, which could provide distinct functional capabilities, such as responding to different ligand variants. While individual pathways have been well-studied, we have lacked a comprehensive understanding of what receptor combinations are expressed and how they are distributed across cell types. Here, combining data from multiple single-cell gene expression atlases, we analyzed the expression profiles of core signaling pathways, including TGF-β, Notch, Wnt, and Eph-ephrin, as well as non-signaling pathways. In many pathways, a limited set of receptor expression profiles are used recurrently in many distinct cell types. While some recurrent profiles are restricted to groups of closely related cells, others, which we term pathway expression motifs, reappear in distantly related cell types spanning diverse tissues and organs. Motif usage was generally uncorrelated between pathways, remained stable in a given cell type during aging, but could change in sudden punctuated transitions during development. These results suggest a mosaic view of pathway usage, in which the same core pathways can be active in many or most cell types, but operate in one of a handful of distinct modes.