| RRC ID |
68425
|
| 著者 |
Nakakuki T, Birtwistle MR, Saeki Y, Yumoto N, Ide K, Nagashima T, Brusch L, Ogunnaike BA, Okada-Hatakeyama M, Kholodenko BN.
|
| タイトル |
Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics.
|
| ジャーナル |
Cell
|
| 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.
|
| 巻・号 |
141(5)
|
| ページ |
884-96
|
| 公開日 |
2010-5-28
|
| DOI |
10.1016/j.cell.2010.03.054
|
| PII |
S0092-8674(10)00373-9
|
| PMID |
20493519
|
| PMC |
PMC2888034
|
| MeSH |
Cell Line, Tumor
Dual-Specificity Phosphatases / metabolism
ErbB Receptors / metabolism
Extracellular Signal-Regulated MAP Kinases / metabolism
Humans
Models, Biological*
Neuregulin-1 / metabolism
Protein Stability
Proto-Oncogene Proteins c-fos / genetics*
Proto-Oncogene Proteins c-fos / metabolism
Transcription, Genetic
|
| IF |
38.637
|
| リソース情報 |
| ヒト・動物細胞 |
PC-12(RCB0009) |
