Journal Article

Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling

Jetka, Tomasz, Schaper, Fred, Billing, Ulrike, Nortmann, Lukas, Waldherr, Steffen, Dittrich, Anna, Wundrack, Nicole, Komorowski, Michal

2019

Overview

Cellular communication via intracellular signalling pathways is crucial. Expression and activation of signalling proteins is heterogenous between isogenic cells of the same cell-type. However, mechanisms evolved to enable sufficient communication and to ensure cellular functions. We use information theory to clarify mechanisms facilitating IL-6-induced JAK/STAT signalling despite cell-to-cell variability. We show that different mechanisms enabling robustness against variability complement each other. Early STAT3 activation is robust as long as cytokine concentrations are low. Robustness at high cytokine concentrations is ensured by high STAT3 expression or serine phosphorylation. Later the feedback-inhibitor SOCS3 increases robustness. Channel Capacity of JAK/STAT signalling is limited by cell-to-cell variability in STAT3 expression and is affected by the same mechanisms governing robustness. Increasing STAT3 amount increases Channel Capacity and robustness, whereas increasing STAT3 tyrosine phosphorylation reduces robustness but increases Channel Capacity. In summary, we elucidate mechanisms preventing dysregulated signalling by enabling reliable JAK/STAT signalling despite cell-to-cell heterogeneity. Billing et al. clarify mechanisms ensuring reliable cytokine signaling despite variable expression and activation of signaling proteins in cells. Limited activation of signaling proteins either by feedback inhibition or low cytokine doses, and STAT3 serine phosphorylation timely orchestrate robustness and capacity of IL-6-induced signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337 / 631/80/86 / Animals / Biomedical and Life Sciences / Cell activation / Cell interactions / Cell Line / Complement activation / Cytokines / Cytokines - metabolism / Dose-Response Relationship, Drug / Feedback inhibition / Fibroblasts - drug effects / Fibroblasts - metabolism / Gene Expression Regulation / Information theory / Interleukin 6 / Interleukin-6 - metabolism / Interleukin-6 - pharmacology / Intracellular signalling / Janus Kinases - metabolism / Life Sciences / Mice / Phosphorylation / Proteins / Serine / Signal transduction / Signal Transduction - drug effects / STAT Transcription Factors - genetics / STAT Transcription Factors - metabolism / Stat3 protein / STAT3 Transcription Factor - metabolism / Suppressor of Cytokine Signaling 3 Protein - metabolism / Tyrosine