Linear Integration of ERK Activity Predominates over Persistence Detection in Fra-1 Regulation

Taryn E. Gillies, Michael Pargett, Marta Minguet, Alex Davies, John G. Albeck

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

ERK signaling regulates the expression of target genes, but it is unclear how ERK activity dynamics are interpreted. Here, we investigate this question using simultaneous, live, single-cell imaging of two ERK activity reporters and expression of Fra-1, a target gene controlling epithelial cell identity. We find that Fra-1 is expressed in proportion to the amplitude and duration of ERK activity. In contrast to previous “persistence detector” and “selective filter” models in which Fra-1 expression only occurs when ERK activity persists beyond a threshold duration, our observations demonstrate that the network regulating Fra-1 expression integrates total ERK activity and responds to it linearly. However, exploration of a generalized mathematical model of the Fra-1 coherent feedforward loop demonstrates that it can perform either linear integration or persistence detection, depending on the basal mRNA production rate and protein production delays. Our data indicate that significant basal expression and short delays cause Fra-1 to respond linearly to integrated ERK activity. Using a combination of live-cell ERK activity reporters and mathematical analysis, Gillies et al. determine that the immediate-early gene, Fra-1, is produced in linear relation to total ERK activity. This demonstrates that the network functions as a linear integrator, not a selective filter, of ERK activity patterns.

Original languageEnglish (US)
Pages (from-to)549-563.e5
JournalCell Systems
Volume5
Issue number6
DOIs
StatePublished - Dec 27 2017

Keywords

  • c-Fos degradation
  • EGF
  • EGFR
  • FOSL1
  • FRET
  • KTR
  • MAPK
  • Ras
  • signal transduction dynamics
  • transcription

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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