Sensing relative signal in the Tgf-β/Smad pathway.
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, andwnt9a) 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.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125 goentoro@caltech.edu cfrick@caltech.edu.
Christopher L
CL
Frick
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Clare
C
Yarka
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Harry
H
Nunns
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125 goentoro@caltech.edu cfrick@caltech.edu.
Lea
L
Goentoro
D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059010:Single-Cell Analysis / Q000379:methods; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
C526317:CCN2 protein, human; D011994:Recombinant Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor
Smad; Tgf-β; fold-change detection; information; signal transduction