Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling
Open accessAbstract
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.
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With increasing Hy-IL-6 amounts, MI is significantly increased compared to unstimulated MEF wt cells.
“With increasing Hy-IL-6 amounts resulting in stronger phosphorylation of STAT3 (Fig. 2b), MI is significantly increased compared to MI in unstimulated MEF wt cells (Fig. 3d, e, blue boxes and *) [20].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
The Results section (‘STAT3-Y705 phosphorylation is robust for weak stimuli’; page unavailable) says mutual information in MEF cells increases with increasing Hy-IL-6 dose until it plateaus. Our copy does not report a statistical comparison with unstimulated MEF cells, so it does not establish the claimed significant increase relative to that baseline. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRobustness of late IL-6-induced JAK/STAT signalling is achieved by expression of SOCS3.
“Robustness of late JAK/STAT signalling is achieved by expression of SOCS3.”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
SOCS3 increases robustness of STAT3-Y705 phosphorylation while reducing Channel Capacity of late JAK/STAT signalling.
“While it increases robustness of STAT3-Y705 phosphorylation it reduces Channel Capacity of late JAK/STAT signalling [20].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
When SOCS3 is expressed, it reduces STAT3 phosphorylation and increases robustness.
“When SOCS3 is expressed it reduces STAT3 phosphorylation and increases robustness [20] while SHP2 no longer contributes to robustness.”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
Early JAK/STAT signalling is robust as long as STAT3 phosphorylation is low and STAT3 expression is high.
“Early JAK/STAT signalling is robust as long as STAT3 phosphorylation is low (e.g. because of low cytokine concentration) and STAT3 expression is high.”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
STAT3 expression is heterogeneous within the MEF wt cell population.
“As shown earlier [20] single cell flow cytometry analyses of STAT3 reveal considerable differences in STAT3 expression within the MEF wt cell population, indicating that individual cells differ strongly in respect to STAT3 protein expression (Fig. 2a).”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
Information transfer through the JAK/STAT pathway is strongly reduced at late timepoints, which reflects reduced activation of STAT3 at late time points.
“As shown earlier [20] information transfer through the JAK/STAT pathway is strongly reduced at late timepoints, which reflects reduced activation of STAT3 at late time points.”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
This seems to complement the function of SOCS3, which controls robustness of late IL-6-induced STAT3 activation.
“This seems to complement the function of SOCS3, which controls robustness of late IL-6-induced STAT3 activation [20].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
Channel Capacity of IL-6-induced JAK/STAT signalling is restricted by heterogeneity of STAT3 expression and at late time points by expression of SOCS3.
“Channel Capacity of IL-6-induced JAK/STAT signalling in general is restricted by heterogeneity of STAT3 expression and in particular at late time points by expression of SOCS3 [20].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
Serin phosphorylation contributes to reduction of STAT3 Y705 phosphorylation, thereby increasing robustness of STAT3 Y705 phosphorylation to varying STAT3 expression.
“Serin phosphorylation contributes to reduction of STAT3 Y705 phosphorylation [46], thereby increasing robustness of STAT3 Y705 phosphorylation to varying STAT3 expression [20].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
Mechanisms that reduce IL-6-induced STAT3-Y705 phosphorylation such as expression of SOCS3 and STAT3-S727 phosphorylation increase robustness of signalling against varying STAT3 expression but reduce the amount of information transferred through IL-6-induced JAK/STAT signalling.
“Mechanisms that reduce IL-6-induced STAT3-Y705 phosphorylation such as expression of SOCS3 and STAT3-S727 phosphorylation on the one hand increase robustness of signalling against varying STAT3 expression. On the other hand, these mechanisms reduce the amount of information transferred through IL-6-induced JAK/STAT signalling.”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
STAT3 expression and phosphorylation are highly heterogeneous in isogenic cell populations, and this heterogeneity affects robustness and information transfer of IL-6-induced JAK/STAT signalling.
“We have recently shown that both STAT3 expression and phosphorylation are highly heterogeneous in isogenic cell populations. This heterogeneity affects robustness and information transfer of IL-6-induced JAK/STAT signalling [20].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
Channel Capacity of IL-6-induced JAK/STAT signalling is below 1 bit.
“We confirmed in this study, that Channel Capacity of IL-6-induced JAK/STAT signalling is below 1 bit (Fig. 6a) [20].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
SOCS3 reduces Channel Capacity of IL-6-induced JAK/STAT signalling, while SHP2 increases it.
“While SOCS3 reduces Channel Capacity of IL-6-induced JAK/STAT signalling [20], SHP2 increases it (Fig. 6a).”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [20]
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Lampert, E. J., Zimmer, A., Padget, M., Cimino-Mathews, A., Nair, J. R., Liu, Y., Swisher, E. M., Hodge, J. W., Nixon, A. B., Nichols, E., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-0056 · Cited by 220 · see citing works
Fiebelkow, J., Guendel, A., Guendel, B., Mehwald, N., Jetka, T., Komorowski, M., Waldherr, S., Schaper, F., & Dittrich, A. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00770-7 · Cited by 53 · see citing works
“While it increases robustness of STAT3-Y705 phosphorylation it reduces Channel Capacity of late JAK/STAT signalling [20].”
BackgroundMethodInfluentialSelf-citation
- Authors
- Billing, U., Jetka, T., Nortmann, L., Wundrack, N., Komorowski, M., Waldherr, S., Schaper, F., & Dittrich, A.
- Affiliations
- Otto-von-Guericke-Universität Magdeburg (DE)
- Institute of Fundamental Technological Research (PL)
- KU Leuven (BE)
- Corresponding author
- Dittrich, Anna
- ORCID
- Venue
- Communications Biology
- Published
- 2019-01-18
- Volume
- 2
- Issue
- 1
- Pages
- 27-27
- ISSN
- 2399-3642 (ISSN-L)
- PMC
- PMC6338669
- OpenAlex
- W2910137290
- Cited by
- 64
- References
- 5
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 8 · 2023: 13 · 2022: 8 · 2021: 10 · 2020: 5 · 2019: 1
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Communications Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Digitalen Hochschulbibliothek Sachsen-Anhalt (Universitäts- und Landesbibliothek Sachsen-Anhalt) (cc-by)
- Funders
- European Commission (334298)
- Bundesministerium für Bildung und Forschung
- Research Executive Agency
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- IL-6 signaling, JAK/STAT signaling, STAT3, robustness, cell-to-cell variability, information theory, channel capacity, SOCS3, serine phosphorylation, tyrosine phosphorylation, product inhibition, cytokine concentration
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Cell Line, Dose-Response Relationship, Drug, Fibroblasts, Gene Expression Regulation, Phosphorylation, Signal Transduction, Interleukin-6, Cytokines, STAT Transcription Factors, STAT3 Transcription Factor, Mice, Janus Kinases
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