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

Takashi Nakakuki, Marc R. Birtwistle, Yuko Saeki, Noriko Yumoto, Kaori Ide, Takeshi Nagashima, Lutz Brusch, Babatunde A. Ogunnaike, Mariko Okada-Hatakeyama, Boris N. Kholodenko

Research output: Contribution to journalArticlepeer-review

159 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)884-896
Number of pages13
JournalCell
Volume141
Issue number5
DOIs
Publication statusPublished - 2010 May

Keywords

  • Signaling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Ligand-specific c-fos expression emerges from the spatiotemporal control of ErbB network dynamics'. Together they form a unique fingerprint.

Cite this