Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics.
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.
Nakakuki
Takashi
T
Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, 1-7-22 Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Birtwistle
Marc R
MR
Saeki
Yuko
Y
Yumoto
Noriko
N
Ide
Kaori
K
Nagashima
Takeshi
T
Brusch
Lutz
L
Ogunnaike
Babatunde A
BA
Okada-Hatakeyama
Mariko
M
Kholodenko
Boris N
BN
D045744:Cell Line, Tumor; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D020890:Neuregulin-1 / Q000378:metabolism; D055550:Protein Stability; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D020890:Neuregulin-1; D016760:Proto-Oncogene Proteins c-fos; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D054637:Dual-Specificity Phosphatases