%0 Journal Article
%T Liebig's law of the minimum in the TGF-β/SMAD pathway.
%A Li Y
%A Deng D
%A Höfer CT
%A Kim J
%A Do Heo W
%A Xu Q
%A Liu X
%A Zi Z
%J PLoS Comput Biol
%V 20
%N 5
%D 2024 May 16
%M 38753874
%F 4.779
%R 10.1371/journal.pcbi.1012072
%X 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.