Figure 3

Reaction network of the IFNγ stimulated STAT1 signaling pathway. The network shows key reactions of the pathway, which are translated into a mathematical model. IFNγ activates the receptor Ir. To keep the model simple, Janus kinases are not considered separately but as part of the active receptor complex IIr only. IIr phosphorylates unphosphorylated cytosolic STAT1 (STAT1Uc), followed by rapid formation of homodimers (STAT1Dc). STAT1Dc translocates into the nucleus (STAT1Dn) and induces the transcription of specific target genes by binding to the DNA (STAT1Dnd). When dimerized nuclear STAT1 is not bound to the DNA, dimers may dissociate, followed by protein dephosphorylation and nuclear export of the resulting STAT1Un [27]. STAT1Uc can also shuttle into the nucleus [32]. The network considers SOCS1 as a potential negative feedback regulator inhibiting the phosphorylation of STAT1Uc [28, 29] and STAT1 itself as target genes of IFNγ-activated signaling [10]. The annotation time delay refers to temporal differences between IFNγ action at the receptor level and consecutive steps. The level of phosphorylated STAT1 did not decrease despite induction of SOCS1 expression (Fig. 5). This observation suggests that the negative feedback could be effective at late times (≥ 180 min) only, where it could reduce the slope of the late increase of phosphorylated STAT1. In comparison to the network previously established for stellate cells [10], only two reactions were changed: Since the experimental data showed no decrease of STAT1 phosphorylation, IFNγ degradation and receptor deactivation were neglected.