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2017 ; 114
(14
): E2975-E2982
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Sensing relative signal in the Tgf-?/Smad pathway
#MMPMID28320972
Frick CL
; Yarka C
; Nunns H
; Goentoro L
Proc Natl Acad Sci U S A
2017[Apr]; 114
(14
): E2975-E2982
PMID28320972
show ga
How signaling pathways function reliably despite cellular variation remains a
question in many systems. In the transforming growth factor-? (Tgf-?) pathway,
exposure to ligand stimulates nuclear localization of Smad proteins, which then
regulate target gene expression. Examining Smad3 dynamics in live reporter cells,
we found evidence for fold-change detection. Although the level of nuclear Smad3
varied across cells, the fold change in the level of nuclear Smad3 was a more
precise outcome of ligand stimulation. The precision of the fold-change response
was observed throughout the signaling duration and across Tgf-? doses, and
significantly increased the information transduction capacity of the pathway.
Using single-molecule FISH, we further observed that expression of Smad3 target
genes (ctgf, snai1, and wnt9a) correlated more strongly with the fold change,
rather than the level, of nuclear Smad3. These findings suggest that some target
genes sense Smad3 level relative to background, as a strategy for coping with
cellular noise.
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