Abstract
Different dynamic behaviours of signalling activity can induce distinct biological responses in a variety of cells. However, the molecular mechanisms that determine the dynamics of kinase activities in immune cells are not well understood. In this study, we showed that the duration of both IκB kinase (IKK) and extracellular signal-regulated kinase (ERK) activities in B cell receptor (BCR)- and CD40-signalling pathways in B cells were regulated by transcriptional feedback loops. We conducted a time-course transcriptome analysis after BCR or CD40 stimulation and identified the following four candidate genes as feedback regulators for IKK and ERK: inhibitor of apoptosis protein (IAP), TNF alpha-induced protein 3, dual-specificity phosphatase 5, and sprouty homolog 2. Quantitative experiments and mathematical modelling suggested that IAP inhibition shortened the duration of IKK and ERK activity following both BCR and CD40 pathway stimulation, indicating a positive role for IAP in B cell signalling. Furthermore, transient kinase activities induced by IAP blockage reduced the levels of delayed expression genes. Together, our findings suggest that IKK and ERK activity durations can be fine-tuned by the coordinated regulation of positive and negative transcriptional feedback and that these network properties determine the biological output of B cells.
Highlights
The duration of kinase activity is crucial in deciding the fate of mammalian cells
We showed that the dynamics of extracellular signal-regulated kinase (ERK) and IKK activities in response to B cell receptor (BCR)- and CD40stimulation were distinct, but that they could both be positively modulated by the induction of inhibitor of apoptosis protein (IAP)
We examined the dynamics of ERK and IKK activities over time following BCR or CD40 stimulation with anti-IgM or CD40 ligands, respectively (Fig. 1, Supplementary Fig. S1)
Summary
It is widely known that the transient and sustained activation of extracellular signal-regulated kinase (ERK) induces the proliferation and differentiation of many types of cells[1,2,3,4,5,6] and that prolonged IκB kinase (IKK) activity is required for stimulus-specific gene expression programs[7]. The BCR and CD40 signalling pathways share IKK-nuclear factor (NF)κB22 and ERK core modules These two signalling activities are crucial for B cell activation processes[23,24] and are controlled by feedback regulation. Dual-specificity phosphatase (DUSP) is known to have a similar function in controlling ERK24,25 These genes are expressed very early in the response to cell stimulation, thereby enabling control of the dynamics of upstream signalling pathways. Our studies suggest that the dynamic cross-talk between signalling and transcription processes is important to determine the B cell gene expression output that is involved in the immune response
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