Sensing relative signal in the Tgf-β/Smad pathway
Christopher L. Frick a,1, Clare Yarka a, Harry Nunns a, and Lea Goentoro a,1
a Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
Edited by Arup K. Chakraborty, Massachusetts Institute of Technology, Cambridge, MA, and approved February 3, 2017 (received for review July 12, 2016)
It is not fully understood how cells process information in the face of noise. We posed this question in the transforming growth factor-β (Tgf-β) pathway, a major intercellular signaling pathway in animal cells. We found evidence that rather than sensing the signaling state of the Tgf-β pathway, cells sense the signaling state relative to background. Finding that signaling dynamics are interpreted in a relative manner may have implications for how we understand the pathway’s context-dependent outcomes and roles in diseases. Our work reinforces an emerging principle that individual cells process signal in a relative manner.
How signaling pathways function reliably despite cellular variation remains a question in many systems. In the transforming growth factor-β (Tgf-β) 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-β 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.
signal transduction fold-change detection Tgf-β Smad information
1 To whom correspondence may be addressed. Email: firstname.lastname@example.org or email@example.com.
Author contributions: C.L.F. and L.G. designed research; C.L.F. and C.Y. performed research; H.N. contributed new reagents/analytic tools; C.L.F. and C.Y. analyzed data; and C.L.F. and L.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1611428114/-/DCSupplemental.
Freely available online through the PNAS open access option.
FREE PDF GRATIS: PNAS