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Cell. 2010 May 28;141(5):884-96. doi: 10.1016/j.cell.2010.03.054. Epub 2010 May 20.

Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics.

Author information

1
Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, 1-7-22 Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.

Abstract

Activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) determines distinct cell-fate decisions, although signals propagate through shared pathways. Using mathematical modeling and experimental approaches, we unravel how HRG and EGF generate distinct, all-or-none responses of the phosphorylated transcription factor c-Fos. In the cytosol, EGF induces transient and HRG induces sustained ERK activation. In the nucleus, however, ERK activity and c-fos mRNA expression are transient for both ligands. Knockdown of dual-specificity phosphatases extends HRG-stimulated nuclear ERK activation, but not c-fos mRNA expression, implying the existence of a HRG-induced repressor of c-fos transcription. Further experiments confirmed that this repressor is mainly induced by HRG, but not EGF, and requires new protein synthesis. We show how a spatially distributed, signaling-transcription cascade robustly discriminates between transient and sustained ERK activities at the c-Fos system level. The proposed control mechanisms are general and operate in different cell types, stimulated by various ligands.

PMID:
20493519
PMCID:
PMC2888034
DOI:
10.1016/j.cell.2010.03.054
[Indexed for MEDLINE]
Free PMC Article

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