Ligand-Specific c-Fos Expression Emerges from the Spatiotemporal Control of ErbB Network Dynamics

Abstract

Summary Activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) determines distinct cell fate decisions, although signals propagate through shared pathways. Using modeling and experiments, we unravel how EGF and HRG 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.

Complexity of Receptor Tyrosine Kinase Signal Processing

“…Indeed, by sequestering Cdc42, Mig-6 inhibits hepatocyte growth factor (HGF)-induced cell migration (Gotoh 2009 (Camps et al 1998). The class I DUSPs (1/2/4/5) are inducible nuclear phosphatases, whose expression can be detected within an hour after activation of the ErbB receptors (Owens and Keyse 2007;Nakakuki et al 2010). A recent study found transient ERK activity in the nucleus, whereas ERK activity in the cytoplasm was sustained.…”

“…A recent study found transient ERK activity in the nucleus, whereas ERK activity in the cytoplasm was sustained. These different ERK kinetics in the cytoplasm and the nucleus were explained by inducible expression of several nuclear DUSPs since simultaneous knockdown of these phosphatases substantially prolonged ERK activation in the nucleus (Nakakuki et al 2010).…”

“…2B) (Murphy et al 2002(Murphy et al , 2004Nakakuki et al 2010). This mechanism of discrimination between transient and sustained ERK activity at the IEG level is common for different RTKs and cell types and may lead to distinct cell-fate decisions, such as proliferation or tumorigenicity (Nakakuki et al 2010).…”

“…The concept is emerging that for any RTK pathway, there is no single protein or gene responsible for signaling specificity. Rather, specificity is determined by the spatiotemporal dynamics of activation of signaling proteins, IEGs, and DEGs, downstream of RTKs (Murphy et al 2004;Kholodenko 2006;Nakakuki et al 2010). Yet many signaling events activated by RTKs are partially redundant, and different RTKs can compensate for each other in many cellular functions (Xu and Huang 2010).…”

On the personalised modelling of cancer signalling * *Supported by EU FP7 grant “SynSignal” (No. 613879).

“…Regulation of gene expression on the level of mRNA and total protein is quite common (Kolch et al, 2015;Nakakuki et al, 2010). Examples that are particularly relevant for cancer are regulation of the cell-cycle or the DNA-damage response.…”