Journal
CELL SYSTEMS
Volume 9, Issue 6, Pages 580-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2019.11.005
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Funding
- NIH [1U54CA209988, U54-HG008100]
- Prospect Creek Foundation
- Jayne Koskinas Ted Giovanis Foundation for Health and Policy
- Breast Cancer Research Foundation
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Cells sense and respond to signals in their local environment by activating signaling cascades that lead to phenotypic changes. Differences in these signals can be discriminated at the population level; however, single cells have been thought to be limited in their capacity to distinguish ligand doses due to signaling noise. We describe here the rational development of a genetically encoded FoxO1 sensor, which serves as a down-stream readout of insulin growth factor-phosphatidylinositol 3-kinase IGF-PI3K-AKT signaling pathway activity. With this reporter, we tracked individual cell responses to multiple IGF-I doses, pathway inhibitors, and repeated treatments. We observed that individual cells can discriminate multiple IGF-I doses, and these responses are sustained over time, are reproducible at the single-cell level, and display cell-to-cell heterogeneity. These studies imply that cell-to-cell variation in signaling responses is biologically meaningful and support the endeavor to elucidate mechanisms of cell signaling at the level of the individual cell.
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