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

Nakakuki, Takashi; Birtwistle, Marc R; Saeki, Yuko; Yumoto, Noriko; Ide, Kaori; Nagashima, Takeshi; Brusch, Lutz; Ogunnaike, Babatunde A; Okada-Hatakeyama, Mariko; Kholodenko, Boris N.
Cell; 141(5): 884-96, 2010 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-20493519
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.
Selo DaSilva