Liebig's law of the minimum in the TGF-β/SMAD pathway.

Cells use signaling pathways to sense and respond to their environments. The transforming growth factor-β (TGF-β) pathway produces context-specific responses. Here, we combined modeling and experimental analysis to study the dependence of the output of the TGF-β pathway on the abundance of signaling molecules in the pathway. We showed that the TGF-β pathway processes the variation of TGF-β receptor abundance using Liebig's law of the minimum, meaning that the output-modifying factor is the signaling protein that is most limited, to determine signaling responses across cell types and in single cells. We found that the abundance of either the type I (TGFBR1) or type II (TGFBR2) TGF-β receptor determined the responses of cancer cell lines, such that the receptor with relatively low abundance dictates the response. Furthermore, nuclear SMAD2 signaling correlated with the abundance of TGF-β receptor in single cells depending on the relative expression levels of TGFBR1 and TGFBR2. A similar control principle could govern the heterogeneity of signaling responses in other signaling pathways. Author summary: The same cell signal can often initiate different signaling responses depending on the cellular context, but the underlying control principle remains unclear. In this study, we explored the complex world of cell signaling, focusing on the transforming growth factor-β (TGF-β) pathway that plays a crucial role in regulating fundamental cellular processes such as cell proliferation, migration and differentiation. We were intrigued by how variations in the abundance of signaling molecules could impact the responses of the TGF-β pathway in different types of cells and within individual cells. Our investigation led to an insightful discovery—the "minority control rule" in the TGF-β pathway, similar to Liebig's law of the minimum. This minority control rule suggests that the activity of TGF-β signaling is governed by the TGF-β receptor present at the lowest level, much like the shortest wood plate determining the capacity of a cask. By uncovering this principle, we shed light on the significance of considering the relative abundance of signaling proteins, especially receptors, in designing strategies aimed at modulating the activities of signaling pathways for therapeutic purposes. [ABSTRACT FROM AUTHOR]