Asymmetric crosstalk between the TGFβ and BMP pathways resolves signaling ambiguity via promiscuous SMAD binding

Signaling pathways play a central role in development, the immune system, and cancer controlling cellular fate decisions. To drive a coordinated response to their environment, cells sense extracellular ligands and activate intracellular second messenger proteins accordingly. The TGFβ and BMP signaling pathways control many biological processes and have shown non-trivial, antagonist interactions. This work aims to develop a quantitative understanding of how cells integrate and interpret multi-ligand signaling. We will systematically map the response of NMuMG cells to various combinations of TGFβ and BMP ligand gradients. Our experimental data reports a new type of pathway crosstalk where TGFβ signaling is increased and simultaneously BMP signaling is suppressed. A simple mathematical model predicts underlying promiscuous SMAD protein interactions between both pathways that have not yet been reported. We will further extend our investigations into ligand pair-dependent variants of this mechanism as well as propose a plan to apply our findings to relevant physiological processes. This work will characterize new principles controlling the way cells perceive and integrate signaling of the TGFβ superfamily and provide deeper understanding into controlling cellular processes.