Asymmetric crosstalk between the BMP and TGF-β pathways resolves signaling ambiguity

The BMP and TGF-β signaling pathways control cellular fate decisions in diverse biological contexts, often playing opposing roles. Despite extensive knowledge of these pathways, understanding how cells respond to environments containing these opposing cues remains a challenge. Here, we systematically analyze the activation of these pathways under combinatorial signaling environments. We find that TGF-β ligands inhibit BMP signaling while BMP ligands enhance TGF-β transcriptional response across concentrations, ligand variants, and cell types. This asymmetric crosstalk results in the activation of a TGF-β-biased transcriptional response even under mixed-signaling conditions, effectively reducing signal ambiguity, with implications for processes such as epithelial-to-mesenchymal transition (EMT). We show that this crosstalk originates downstream of SMAD protein phosphorylation. Using mathematical models, we predict and experimentally verify that promiscuous interactions between SMAD proteins provide the mechanism for the observed crosstalk. Our findings challenge the canonical models, suggesting an active role for mediator proteins in determining biological responses.