State- and stimulus-specific dynamics of SMAD signaling determine fate decisions in individual cells

SMAD-mediated signaling regulates apoptosis, cell cycle arrest, and epithelial-to-mes-enchymal transition to safeguard tissue homeostasis. However, it remains elusive how the relatively simple pathway can determine such a broad range of cell fate decisions and how it differentiates between varying ligands. Here, we systematically investigate how SMAD-mediated responses are modulated by various ligands of the transforming growth factor (3 (TGF(3) family and compare these ligand responses in quiescent and proliferating MCF10A cells. We find that the nature of the phenotypic response is mainly determined by the proliferation status, with migration and cell cycle arrest being dom-inant in proliferating cells for all tested TGF(3 family ligands, whereas cell death is the major outcome in quiescent cells. In both quiescent and proliferating cells, the identity of the ligand modulates the strength of the phenotypic response proportional to the dynamics of induced SMAD nuclear-to-cytoplasmic translocation and, as a consequence, the corresponding gene expression changes. Interestingly, the proliferation state of a cell has little impact on the set of genes induced by SMAD signaling; instead, it modulates the relative cellular sensitivity to TGF(3 superfamily members. Taken together, diversity of SMAD-mediated responses is mediated by differing cellular states, which determine ligand sensitivity and phenotypic effects, while the pathway itself merely serves as a quantitative relay from the cell membrane to the nucleus.

Automated summary

SMAD-mediated signaling regulates cell fate decisions by responding to different ligands of the TGF(3 family, with the nature of the response determined by the proliferation status of the cells. Ligand identity modulates the strength of the response, which is correlated with SMAD nuclear-to-cytoplasmic translocation and gene expression changes. The proliferation state of the cell affects the sensitivity to TGF(3 superfamily members, while the pathway itself serves as a relay from the cell membrane to the nucleus.