CoChat
Sign Up
Cited by 53Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesGene Regulatory Network Analysis

The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling

Open access
Fiebelkow, Jessica, Guendel, André, Guendel, Beate, Mehwald, Nora, Jetka, Tomasz, Komorowski, Michal, Waldherr, Steffen, Schaper, Fred +1 more·2021·Cell Communication and Signaling
DOI 10.1186/s12964-021-00770-7PMC PMC8444181
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Cell-to-cell heterogeneity is an inherent feature of multicellular organisms and is central in all physiological and pathophysiological processes including cellular signal transduction. The cytokine IL-6 is an essential mediator of pro- and anti-inflammatory processes. Dysregulated IL-6-induced intracellular JAK/STAT signalling is associated with severe inflammatory and proliferative diseases. Under physiological conditions JAK/STAT signalling is rigorously controlled and timely orchestrated by regulatory mechanisms such as expression of the feedback-inhibitor SOCS3 and activation of the protein-tyrosine phosphatase SHP2 (PTPN11). Interestingly, the function of negative regulators seems not to be restricted to controlling the strength and timely orchestration of IL-6-induced STAT3 activation. Exemplarily, SOCS3 increases robustness of late IL-6-induced STAT3 activation against heterogenous STAT3 expression and reduces the amount of information transferred through JAK/STAT signalling. Methods: Here we use multiplexed single-cell analyses and information theoretic approaches to clarify whether also SHP2 contributes to robustness of STAT3 activation and whether SHP2 affects the amount of information transferred through IL-6-induced JAK/STAT signalling. Results: SHP2 increases robustness of both basal, cytokine-independent STAT3 activation and early IL-6-induced STAT3 activation against differential STAT3 expression. However, SHP2 does not affect robustness of late IL-6-induced STAT3 activation. In contrast to SOCS3, SHP2 increases the amount of information transferred through IL-6-induced JAK/STAT signalling, probably by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells. These effects are independent of SHP2-dependent MAPK activation. Conclusion: In summary, the results of this study extend our knowledge of the functions of SHP2 in IL-6-induced JAK/STAT signalling. SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information. Plain English summary Cells within a multicellular organism communicate with each other to exchange information about the environment. Communication between cells is facilitated by soluble molecules that transmit information from one cell to the other. Cytokines such as interleukin-6 are important soluble mediators that are secreted when an organism is faced with infections or inflammation. Secreted cytokines bind to receptors within the membrane of their target cells. This binding induces activation of an intracellular cascade of reactions called signal transduction, which leads to cellular responses. An important example of intracellular signal transduction is JAK/STAT signalling. In healthy organisms signalling is controlled and timed by regulatory mechanisms, whose activation results in a controlled shutdown of signalling pathways. Interestingly, not all cells within an organism are identical. They differ in the amount of proteins involved in signal transduction, such as STAT3. These differences shape cellular communication and responses to intracellular signalling. Here, we show that an important negative regulatory protein called SHP2 (or PTPN11) is not only responsible for shutting down signalling, but also for steering signalling in heterogeneous cell populations. SHP2 increases robustness of STAT3 activation against variable STAT3 amounts in individual cells. Additionally, it increases the amount of information transferred through JAK/STAT signalling by increasing the dynamic range of pathway activation in heterogeneous cell populations. This is an amazing new function of negative regulatory proteins that contributes to communication in heterogeneous multicellular organisms in health and disease.

AI snapshot

Written from the paper’s full text.

TL;DR

SHP2 (PTPN11) increases robustness of basal and early IL-6-induced STAT3 activation against cell-to-cell variation in STAT3 expression, but does not affect robustness of late IL-6-induced STAT3 activation. Unlike SOCS3, SHP2 increases the amount of information transferred through early IL-6-induced JAK/STAT signalling, likely by reducing basal cytokine-independent STAT3 phosphorylation and increasing sensitivity.

Key findings

  • SHP2 mutation (MEF SHP2 ΔEx3) increased Hy-IL-6-induced STAT3-Y705 phosphorylation compared with MEF wildtype; reconstitution with wt SHP2 reversed this, confirming SHP2 as a negative regulator of IL-6-induced STAT3 activation.
  • SHP2 increased robustness of basal cytokine-independent STAT3 activation and early (15 min) Hy-IL-6-induced STAT3 activation against differential STAT3 expression; mutation of SHP2 significantly reduced robustness independently of Hy-IL-6 dose, and reconstitution restored it.
  • SHP2 did not affect robustness of late (90 min) Hy-IL-6-induced STAT3 activation; no significant differences were observed between genotypes.
  • Channel Capacity of early Hy-IL-6-induced JAK/STAT signalling was approximately 0.7 bit in MEF wt cells and significantly reduced to 0.3 bit when SHP2 was mutated; reconstitution partly restored it. Late Channel Capacity was not affected by SHP2 mutation.
  • Inhibition of MAPK with U0126 did not affect robustness or Channel Capacity of IL-6-induced JAK/STAT signalling, indicating these SHP2 effects are independent of SHP2-dependent MAPK activation.

Methods

  • Murine embryonal fibroblasts (MEF wt, MEF SHP2 ΔEx3, and MEF SHP2 ΔEx3 + SHP2) were stimulated with Hyper-IL-6 (Hy-IL-6) for 15 min (early) or 90 min (late), with or without the MEK inhibitor U0126.
  • Multiplexed single-cell flow cytometry measured STAT3 expression and STAT3-Y705 phosphorylation simultaneously; Western blotting assessed STAT3, SHP2, SOCS3, ERK1/2, and tubulin/HSC70.
  • Mutual Information (MI) quantified dependency between STAT3 expression and STAT3 phosphorylation as a robustness measure; Channel Capacity (CC) quantified maximal information transfer between Hy-IL-6 concentration and STAT3 phosphorylation, using custom Python/scipy and R SLEMI implementations.

Limitations

  • The paper does not include a dedicated limitations section; stated future work includes addressing how robustness of MAPK signalling is achieved and whether SHP2 contributes to robustness and information transfer of MAPK signalling.
  • Evident from the text: analyses are restricted to MEF cell lines and selected time points (15 min and 90 min), so temporal dynamics and other cell types are not covered.
  • Evident from the text: Channel Capacity was below 1 bit and measured at single time points; the authors note that information transfer is higher when signalling dynamics and multiple outputs are considered.
  • Evident from the text: MAPK involvement was tested pharmacologically with U0126, not by genetic perturbation, and the study does not resolve direct dephosphorylation targets of SHP2 within JAK/STAT signalling.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s12964-021-00770-7

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

29 of 44 cited sources checked · 18 supported · 1 flagged · accuracy not yet measured

  • Findingcitation

    Hy-IL-6-induced STAT3-Y705 phosphorylation is increased in MEF SHP2 ΔEx3 cells compared to MEF wildtype (wt) cells.

    “In accordance with previously published results [13], Hy-IL-6-induced STAT3-Y705 phosphorylation is increased in MEF SHP2 ΔEx3 cells compared to MEF wildtype (wt) cells (Fig. 1a).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, et al. SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem. 2003;278(1):661–71. source

      In “SHP2 Contributes to the Attenuation of Interleukin-6 Signal” (Fig. 1B; page unavailable), the paper reports enhanced STAT3 DNA-binding activity in exon-3-mutant murine fibroblasts versus wild-type cells after stimulation with IL-6 and soluble IL-6R. It does not report STAT3-Y705 phosphorylation for that fibroblast comparison. Its Y705-phosphorylation experiment (Fig. 2B; page unavailable) instead uses IL-5-stimulated COS-7 cells expressing catalytically inactive SHP2 mutants. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • Rests on an assumption: The MEF SHP2 ΔEx3 mutation mimics a SHP2 knock-out.
  • Premisecitation

    Robustness 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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source
  • Premisecitation

    SHP2 is crucial for IL-6-induced activation of the MAPK pathway.

    “Beside it´s function as negative regulator of JAK/STAT signalling SHP2 is crucial for IL-6-induced activation of mitogen-activated protein kinase (MAPK) pathway [8, 14].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE Jr, Yancopoulos GD. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995;267(5202):1349–53. source
    • cites [14] Schiemann WP, Bartoe JL, Nathanson NM. Box 3-independent signaling mechanisms are involved in leukemia inhibitory factor receptor alpha- and gp130-mediated stimulation of mitogen-activated protein kinase Evidence for participation of multiple signaling pathways which converge at Ras. J Biol Chem. 1997;272(26):16631–6. source

      The Results and Discussion (page unavailable) suggest that SHP2 contributes to gp130- and LIFR-mediated MAPK activation. But the experiments used G-CSF-stimulated chimeric receptors, not IL-6 stimulation, and the paper describes SHP2's role as likely and partial rather than establishing it as crucial for IL-6-induced activation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source
  • Findingown data

    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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

      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 measured
    • Rests on an assumption: Protein expression, including expression of signalling proteins, is highly heterogeneous even in isogenic cells from the same tissue or organ.
    • Rests on an assumption: Cell-to-cell heterogeneity shapes activation and inactivation of signalling pathways.
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Premisecitation

    SOCS3 expression is induced in response to STAT3 activation and therefore SOCS3 is only active in late IL-6-induced signalling.

    “SOCS3 expression is induced in response to STAT3 activation [4] and therefore SOCS3 is only active in late IL-6-induced signalling [5].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [4] Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, et al. A family of cytokine-inducible inhibitors of signalling. Nature. 1997;387(6636):917–21. source
    • cites [5] Fischer P, Lehmann U, Sobota RM, Schmitz J, Niemand C, Linnemann S, et al. The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling. Biochem J. 2004;378(Pt 2):449–60. source

      Citation [5] is attached to the claim that SOCS3 is active only in late IL-6 signalling. In “Kinetics of SOCS1 and SOCS3 induction resemble that of IL-6 desensitization” (page not provided), the paper instead reports that SOCS3 protein was detectable very early and describes SOCS3 as an IL-6-induced immediate-early gene. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SHP2 is a repressor of basal cytokine-independent STAT3 phosphorylation.

    “Additionally, SHP2 is a repressor of basal cytokine-independent STAT3 phosphorylation [12, 13].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [12] Dittrich A, Quaiser T, Khouri C, Görtz D, Mönnigmann M, Schaper F. Model-driven experimental analysis of the function of SHP-2 in IL-6-induced Jak/STAT signaling. Mol Biosyst. 2012;8(8):2119–34. source
    • cites [13] Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, et al. SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem. 2003;278(1):661–71. source

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

  • May combine two claims.

    Premisecitation

    SHP2 is rapidly recruited to gp130 and phosphorylated by JAKs, which hints to a function as early feedback inhibitor.

    “In response to IL-6 SHP2 is rapidly recruited to gp130 [8] and phosphorylated by JAKs [11], which hints to a function as early feedback inhibitor.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [8] Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE Jr, Yancopoulos GD. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995;267(5202):1349–53. source
    • cites [11] Schaper F, Gendo C, Eck M, Schmitz J, Grimm C, Anhuf D, et al. Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression. Biochem J. 1998;335(Pt 3):557–65. source

      The Introduction reports transient SHP2 phosphorylation alongside gp130 activation and SHP2–gp130 complex formation, and describes SHP2 as inhibitory. In “SHP2 phosphorylation requires specific Jaks,” the paper finds that Jak1 is required but says it cannot determine whether Jak1 phosphorylates SHP2 directly or another kinase does so. Thus it supports JAK-dependent phosphorylation, but not an unqualified claim that JAKs themselves phosphorylate SHP2. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

  • May combine two claims.

    Premisecitation

    SHP2 has a dual function in IL-6-induced signalling: it reduces JAK/STAT signalling and is indispensable for IL-6-induced MAPK pathway activation.

    “SHP2 has a dual function in IL-6-induced signalling. While it reduces JAK/STAT signalling it is indispensable for IL-6-induced MAPK pathway activation [32, 33].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [32] Eulenfeld R, Dittrich A, Khouri C, Müller PJ, Mütze B, Wolf A, et al. Interleukin-6 signalling: more than Jaks and STATs. Eur J Cell Biol. 2012;91(6–7):486–95. source
    • cites [33] Kim H, Baumann H. Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Mol Cell Biol. 1999;19(8):5326–38. source

      The Abstract states that SHP-2 negatively regulates JAK/STAT signaling and helps mediate gp130-dependent ERK activation in hepatoma cells. But it reports that interfering with SHP-2 reduces ERK activation, not that SHP-2 is indispensable for all IL-6-induced MAPK activation; the claim also omits the hepatic-cell setting. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

  • May combine two claims.

    Interpretationcitation

    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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Inhibition of SOCS3 expression or lack of SOCS3 binding sites in gp130 results in sustained STAT3 activation and altered physiological outcomes in response to IL-6.

    “Inhibition of SOCS3 expression [37] or lack of SOCS3 binding sites in gp130 results in sustained STAT3 activation and altered physiological outcomes in response to IL-6 [38].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [37] Dittrich A, Khouri C, Sackett SD, Ehlting C, Böhmer O, Albrecht U, et al. Glucocorticoids increase interleukin-6-dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor. Hepatology. 2012;55(1):256–66. source
    • cites [38] Schmitz J, Weissenbach M, Haan S, Heinrich PC, Schaper F. SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130. J Biol Chem. 2000;275(17):12848–56. source

      The introductory passage (page unavailable) says mutation of gp130 Tyr-759 produces enhanced and prolonged STAT3 activation and increased gene induction. The SOCS3-binding discussion (page unavailable) also reports that this mutation impairs SOCS3 inhibition of STAT3 and an acute-phase protein gene promoter. These passages support the signaling and gene-expression findings, but do not establish altered physiological outcomes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Interfering with the interaction of SHP2 with PD-1 is a potent alternative to immuno-oncologic approaches aiming to block PD-1 with antibodies in several cancers.

    “Additionally, interfering with the interaction of SHP2 with programmed death-1 (PD-1) is a potent alternative to immuno-oncologic approaches aiming to block PD-1 with antibodies in several cancers [53].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] Fan Z, Tian Y, Chen Z, Liu L, Zhou Q, He J, et al. Blocking interaction between SHP2 and PD-1 denotes a novel opportunity for developing PD-1 inhibitors. EMBO Mol Med. 2020;12(6):e11571. source

      The Impact and Discussion sections describe blocking PD-1/SHP2 interaction as a promising alternative strategy to antibody-based PD-1 inhibition and report a potent inhibitor. The Results report antitumor effects in mouse tumor models, including a lung-cancer model, but do not establish it as an effective alternative in patients with several cancers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [46] Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol. 1997;17(11):6508–16. source
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypermethylation of the SOCS3 promoter and reduced SOCS3 expression is associated with proliferative diseases.

    “Additionally, hypermethylation of the SOCS3 promoter and reduced SOCS3 expression is associated with proliferative diseases [39, 40].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [39] He B, You L, Uematsu K, Zang K, Xu Z, Lee AY, et al. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci U S A. 2003;100(24):14133–8. source
    • cites [40] Sutherland KD, Lindeman GJ, Choong DY, Wittlin S, Brentzell L, Phillips W, et al. Differential hypermethylation of SOCS genes in ovarian and breast carcinomas. Oncogene. 2004;23(46):7726–33. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss-of-function as well as gain-of-function mutations and/or overexpression of SHP2 are found in various diseases such as different cancer types, Noonan syndrome, and LEOPARD syndrome.

    “Loss-of-function as well as gain-of-function mutations and/or overexpression of SHP2 are found in various diseases such as different cancer types [49], Noonan- [50], and LEOPARD-syndrome [51].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [49] Bollu LR, Mazumdar A, Savage MI, Brown PH. Molecular pathways: targeting protein tyrosine phosphatases in cancer. Clin Cancer Res. 2017;23(9):2136–42. source

      The cited paper’s “Phosphatases as Oncogenes” section reports SHP2 overexpression in leukemia and breast cancer, and activating SHP2 mutations associated with childhood leukemias. It does not report loss-of-function SHP2 mutations in cancer. The Noonan and LEOPARD syndrome portions of the citing sentence have separate citations and are not judged here. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [50] Tartaglia M, Gelb BD. Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2005;6:45–68. source
    • cites [51] Yu ZH, Zhang RY, Walls CD, Chen L, Zhang S, Wu L, et al. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry. 2014;53(25):4136–51. source

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling. Commun Biol. 2019;2:27. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    STAT3 expression distribution is independent of Hy-IL-6.

    “The expression and distribution of STAT3 within the cell population are however independent from Hy-IL-6.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IL-6-induced phosphorylation of ERK1/2 was efficiently blocked by U0126, while STAT3 activation was seemingly unaffected.

    “IL-6-induced phosphorylation of ERK1/2 was efficiently blocked by U0126, while STAT3 activation was seemingly unaffected (Fig. 5a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Late Hy-IL-6-induced STAT3 phosphorylation is dose-dependent and heterogeneous but weaker than early STAT3 activation.

    “Late Hy-IL-6-induced STAT3-phosphorylation is dose-dependent and heterogenous (Fig. 4b, d, f) but as also shown in Fig. 1B weaker than early STAT3 activation.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Protein expression, including expression of signalling proteins, is highly heterogeneous even in isogenic cells from the same tissue or organ.
    • Rests on an assumption: Cell-to-cell heterogeneity shapes activation and inactivation of signalling pathways.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    SHP2 reduces robustness of cytokine-independent and early IL-6-induced JAK/STAT signalling against differential STAT3 expression.

    “SHP2 reduces robustness of cytokine-independent and early IL-6-induced JAK/STAT signalling against differential STAT3 expression.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: MEF SHP2 ΔEx3 cells specifically lack SHP2 function and expression of wt SHP2 in these cells restores SHP2 function.

  • May combine two claims.

    Findingown data

    Pharmacological inhibition of MAPK activation reduces neither robustness of IL-6-induced STAT3 phosphorylation nor Channel Capacity of IL-6-induced JAK/STAT signalling.

    “However, pharmacological inhibition of MAPK activation reduces neither robustness of IL-6-induced STAT3 phosphorylation (Fig. 5c) nor Channel Capacity of IL-6-induced JAK/STAT signalling (Fig. 6c).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: U0126 at 10 µM specifically inhibits MEK/MAPK without affecting JAK/STAT signalling.

  • May combine two claims.

    Interpretationreasoning

    Late STAT3 phosphorylation is independent from STAT3 expression and thus robust.

    “supporting the hypothesis that late STAT3 phosphorylation, which is weaker than early STAT3 phosphorylation (Fig. 1b), is independent from STAT3 expression and thus robust.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SOCS3 inhibits JAK activity and thereby contributes to the transient activation profile of STAT3.

    “The negative feedback inhibitor suppressor of cytokine signalling 3 (SOCS3) inhibits JAK activity and thereby contributes to the transient activation profile of STAT3 [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature. 1997;387(6636):921–4. source

  • May combine two claims.

    Interpretationown data

    SHP2 contributes to robustness of basal, cytokine independent STAT3 activation and to robustness of early IL-6-induced STAT3 activation.

    “In summary, SHP2 contributes to robustness of basal, cytokine independent STAT3 activation and to robustness of early IL-6-induced STAT3 activation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein expression, including expression of signalling proteins, is highly heterogeneous even in isogenic cells from the same tissue or organ.
    • Rests on an assumption: Cell-to-cell heterogeneity shapes activation and inactivation of signalling pathways.

  • May combine two claims.

    Interpretationown data

    SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information.

    “SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein expression, including expression of signalling proteins, is highly heterogeneous even in isogenic cells from the same tissue or organ.
    • Rests on an assumption: Cell-to-cell heterogeneity shapes activation and inactivation of signalling pathways.

  • May combine two claims.

    Interpretationreasoning

    The increase in information transfer by SHP2 is probably caused by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells.

    “In contrast to SOCS3, SHP2 increases the amount of information transferred through IL-6-induced JAK/STAT signalling, probably by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein expression, including expression of signalling proteins, is highly heterogeneous even in isogenic cells from the same tissue or organ.
    • Rests on an assumption: Cell-to-cell heterogeneity shapes activation and inactivation of signalling pathways.

  • May combine two claims.

    Interpretationown data

    Based on the results presented here, mutations within PTPN11 and pharmaceutical inhibition of SHP2 probably not only affect strength of intracellular signalling but also induce changes in robustness and information transfer of multiple signalling pathways.

    “Based on the results presented here mutations within PTPN11 and pharmaceutical inhibition of SHP2 probably not only affect strength of intracellular signalling but also induce changes in robustness and information transfer of multiple signalling pathways.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: MEF SHP2 ΔEx3 cells specifically lack SHP2 function and expression of wt SHP2 in these cells restores SHP2 function.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inhibition of SHP2 is seen as a promising strategy for treating several receptor tyrosine kinase-driven cancers.

    “Inhibition of SHP2 is seen as a promising strategy for treating several receptor tyrosine kinase-driven cancers [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Chen YN, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016;535(7610):148–52. source

  • May combine two claims.

    Interpretationown data

    SHP2 increases robustness of basal and early cytokine-induced STAT3 activation, while SOCS3 increases robustness of late cytokine-induced STAT3 activation.

    “While SHP2 increases robustness of basal and early cytokine-induced STAT3 activation (Fig. 3), SOCS3 increases robustness of late cytokine-induced STAT3 activation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: MEF SHP2 ΔEx3 cells specifically lack SHP2 function and expression of wt SHP2 in these cells restores SHP2 function.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SHP2 function is not restricted to IL-6-induced signalling; SHP2 is also a major regulator of signalling induced by other cytokines and growth factors.

    “SHP2 function is not restricted to IL-6-induced signalling but SHP2 is also a major regulator of signalling induced by other cytokines and growth factors [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Tajan M, de Rocca SA, Valet P, Edouard T, Yart A. SHP2 sails from physiology to pathology. Eur J Med Genet. 2015;58(10):509–25. source

  • May combine two claims.

    Interpretationown data

    SHP2 increases robustness and information transfer of early IL-6-induced STAT3-Y705 phosphorylation and ensures independence of basal STAT3 phosphorylation from varying STAT3 expression.

    “In summary, our data highlight new functions of the phosphatase SHP2 in ensuring robust STAT3 activity despite heterogeneous STAT3 expression. SHP2 increases robustness and information transfer of early IL-6-induced STAT3-Y705 phosphorylation and ensures independence of basal STAT3 phosphorylation from varying STAT3 expression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: MEF SHP2 ΔEx3 cells specifically lack SHP2 function and expression of wt SHP2 in these cells restores SHP2 function.

  • May combine two claims.

    Interpretationreasoning

    SOCS3 and SHP2 act in a timely orchestrated manner and complement each other.

    “Of note, SOCS3 and SHP2 act in a timely orchestrated manner and complement each other.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: SHP2 is expressed constitutively.

  • May combine two claims.

    Interpretationown data

    SHP2 does not affect robustness and information transfer of late IL-6-induced JAK/STAT signalling.

    “However, SHP2 does not affect robustness and information transfer of late IL-6-induced JAK/STAT signalling, indicating a timely orchestration of mechanisms that enable cells to cope with cellular heterogeneity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: MEF SHP2 ΔEx3 cells specifically lack SHP2 function and expression of wt SHP2 in these cells restores SHP2 function.
33 of 33

  • The paper relies on this without support.

    It is not known whether SHP2 affects robustness and Channel Capacity of IL-6-induced signalling.

    “So far, it is not known whether the phosphatase SHP2 affects robustness and Channel Capacity of IL-6-induced signalling.”

  • The paper relies on this without support.

    Protein expression, including expression of signalling proteins, is highly heterogeneous even in isogenic cells from the same tissue or organ.

    “Protein expression including the expression of signalling proteins is highly heterogeneous even in isogenic cells from the same tissue or organ.”

  • The paper relies on this without support.

    Cell-to-cell heterogeneity shapes activation and inactivation of signalling pathways.

    “This heterogeneity shapes activation and inactivation of signalling pathways.”

  • The paper relies on this without support.

    MEF cells do not express transmembrane IL-6Rα, so IL-6-induced STAT3 activation in MEF cells depends on trans-signalling enabled by IL-6:sIL-6Rα complexes.

    “MEF cells, like most other cells, do not express transmembrane IL-6Rα. Hence, IL-6-induced STAT3 activation in MEF cells depends on trans-signalling enabled by IL-6:soluble IL-6 receptor α (sIL-6Rα) complexes.”

  • The paper relies on this without support.

    The MEF SHP2 ΔEx3 mutation mimics a SHP2 knock-out.

    “This mutation prevents recruitment of SHP2 to the phosphorylated tyrosine motif 759 within gp130, thereby mimicking a SHP2 knock-out.”

  • The paper relies on this without support.

    SHP2 is expressed constitutively.

    “SHP2 is expressed constitutively, which enables it to act on basal and early IL-6-induced STAT3 activation.”

  • The paper relies on this without support.

    MEF SHP2 ΔEx3 cells specifically lack SHP2 function and expression of wt SHP2 in these cells restores SHP2 function.

    “When SHP2 is mutated (green) Channel Capacity is significantly reduced to 0.3 bit. This reduction is partly restored by expression of wt SHP2 (violet)”

  • The paper relies on this without support.

    U0126 at 10 µM specifically inhibits MEK/MAPK without affecting JAK/STAT signalling.

    “IL-6-induced phosphorylation of ERK1/2 was efficiently blocked by U0126, while STAT3 activation was seemingly unaffected (Fig. 5a).”
8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • SHP2 is said to both reduce and increase robustness

    Minor

    The MAPK section says SHP2 reduces robustness of basal and early signalling, whereas the results section concludes that SHP2 increases robustness in those same phases. The opposing statement reverses a central conclusion.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Fiebelkow, J., Guendel, A., Guendel, B., Mehwald, N., Jetka, T., Komorowski, M., Waldherr, S., Schaper, F., & Dittrich, A.
Affiliations
  • Otto-von-Guericke-Universität Magdeburg (DE)
  • Leibniz-Institut für Pflanzengenetik und Kulturpflanzenforschung (IPK) (DE)
  • Karolinska Institutet (SE)
  • KU Leuven (BE)
Corresponding author
Dittrich, Anna
ORCID
Venue
Cell Communication and Signaling
Publisher
Springer Science and Business Media LLC
Published
2021-09-16
Volume
19
Issue
1
Pages
94-94
ISSN
1478-811X (ISSN-L)
DOI
10.1186/s12964-021-00770-7
PMC
PMC8444181
OpenAlex
W3200950516
Cited by
53
References
55
Citations by year
2026: 14 · 2025: 8 · 2024: 7 · 2023: 12 · 2022: 12
FWCI
2.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Communication and Signaling (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lirias (submittedVersion, other-oa)
  • Europe PMC (PubMed Central) (submittedVersion, other-oa)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Otto-von-Guericke-Universität Magdeburg
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
SHP2, PTPN11, interleukin-6, JAK/STAT signaling, STAT3 activation, signal robustness, information transmission, SOCS3, negative feedback regulation, cellular heterogeneity, single-cell analysis, information theory, MAPK activation, inflammation, signal transduction, cytokine signaling, cell-to-cell communication
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Animals, Cell Communication, Gene Expression Regulation, Humans, Inflammation, Phosphorylation, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, STAT3 Transcription Factor, Cytokine Receptor gp130, Janus Kinases, Protein Tyrosine Phosphatase, Non-Receptor Type 11

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review