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Principles of interleukin (IL)-6-type cytokine signalling and its regulation
Open accessAbstract
The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
Overview
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Written from the paper’s full text.
TL;DR
This review summarizes IL-6-type cytokine signalling through gp130, LIFR and OSMR, covering JAK/STAT and MAPK activation and the mechanisms that terminate or modulate these pathways. It emphasizes negative regulation by tyrosine phosphatases, SOCS feedback inhibitors and PIAS proteins, as well as cross-talk with other signalling cascades.
Key findings
- IL-6-type cytokines (IL-6, IL-11, LIF, OSM, CNTF, CT-1 and CLC) signal via gp130 homodimers or gp130–LIFR/OSMR heterodimers; all potently activate STAT3 and, to a lesser extent, STAT1 through gp130, while OSMR is the most potent activator of STAT5.
- Receptor activation requires more than simple dimerization: efficient gp130 activation by monoclonal antibodies required two distinct antibodies, with the minimal requirement being one intact antibody plus the Fab of a second; insertion of one to four alanines into the gp130 membrane-proximal intracellular region gave full activation only with wild-type and the +3A mutant, interpreted as an approx. 110° twist per alanine and approx. 330° for three.
- JAK1 is essential for IL-6 signalling; gp130, LIFR and OSMR bind JAK1, JAK2 and TYK2. JAK1 mobility is approx. 100-fold lower than that of a typical cytoplasmic protein, and gp130 residues including box1 prolines and Trp666 are critical for JAK binding, while W652A abrogates JAK1 activation without affecting JAK1 association.
- Signal termination involves SHP2 and SOCS3 at gp130 pTyr759, with SOCS3 binding gp130 peptides with slightly higher affinity than SHP2; SOCS1 and SOCS3 inhibit JAKs, PIAS1 inhibits STAT1 and PIAS3 inhibits STAT3. Reported half-lives include SOCS1 1.5 h, SOCS2 1 h, SOCS3 1.6 h, IL-6Rα 2–3 h, gp130 2.5 h, JAK1 3.2 h, JAK2 1.9 h, TYK2 2 h, STAT3α 8.5 h, STAT3β 4.5 h, STAT1 16 h and SHP-2 18–20 h.
Methods
- Narrative review of molecular mechanisms of IL-6-type cytokine signal transduction, focusing on advances made during the previous 5 years in receptor activation, JAK–receptor interactions, STAT activation, signal modulation and cross-talk.
- Synthesizes structural, mutagenesis, biochemical and in vivo findings from the literature; no primary experimental dataset is presented, and the text includes models and a table of half-lives drawn from cited studies.
Limitations
- The authors state that key structural data are still missing, including the structure and conformational states of the cytoplasmic parts of cytokine receptors, and that three-dimensional structures of JAKs and SOCS proteins would be extremely valuable.
- The authors state that mathematical models of this complexity suffer from a lack of sufficient quantitative experimental data, and that cross-talk and biological outcomes depend on cell type and differentiation state.
- Evident from the text: as a narrative review, it does not use a systematic search or meta-analysis, and it includes unpublished work/personal communications and unresolved conflicting findings, such as JNK versus p38 involvement in STAT3 Ser727 phosphorylation and the positive versus negative regulatory functions reported for STAT3β.
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Claims the paper makes
172 Sources not found · 17 Own interpretation · 16 No basis given · 7 Not checked yet · 2 Own result
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In the paper
“Human OSM has the exceptional capability to recruit two different receptor complexes.It forms both LIFR-gp130 and OSMR-gp130 heterodimers.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“LIF and OSM directly engage their signalling receptor subunits without requirement for additional α-receptor subunits (Figure 2) [4,6].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“Soluble forms of cytokine receptors in vivo are formed either by limited proteolysis (shedding) of membrane-bound receptors or by translation from an alternatively spliced mRNA [4].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“It has been demonstrated that sIL-6Rα potentiates the antagonistic activity of sgp130.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“In contrast with IL-6, and presumably also IL-11, where all the helices are straight, the A helix of LIF, OSM and CNTF is kinked [17,18].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“The minimal requirement for receptor activation is one intact antibody and the Fab (fragment antigen binding) of the second antibody.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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In the paper
“It has been shown that these domains are necessary for coupling ligand binding and signal transduction, since deletion of these domains leads to signalling incompetent receptors [36,37].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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“Thus in the homodimer two different binding epitopes of gp130 are involved in ligand recognition [23].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“The interaction sites predicted by mutagenesis studies have recently been confirmed by the X-ray structure of KSHV-IL-6 bound to a soluble gp130 fragment comprising the CBM and the Ig-like domain [24].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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“In contrast with the α-receptors, the receptors that initiate signal transduction have three additional membrane-proximal FNIII domains [4].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“This structural divergence might reflect differences in the mechanisms of receptor recruitment, since the straight cytokines signal via gp130 homodimers, whereas the kinked cytokines signal via LIFR-gp130 or OSMR-gp130 heterodimers.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“Of these, JAK1 plays an essential role, because in cells lacking JAK1 IL-6 signal transduction is greatly impaired [51,52,134].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“This finding has been interpreted in a way that the bivalent intact antibody enforces receptor dimerization and the monovalent Fab adjusts the conformation required for JAK activation and downstream signalling [40].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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In the paper
“Some evidence has been provided that under certain circumstances gp130 and LIFR are degraded after internalization [30][31][32].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“While for gp130, the STATs were found to depend on a specific conformation in order to become phosphorylated, for the EpoR the receptor phosphorylation seems to be sensitive to changes in orientation.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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In the paper
“KSHV-IL-6 binds the gp130 homodimer in the absence of any α-receptor [16], but with lower affinity as compared with IL-6-IL-6Rα-gp130 ternary complexes.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“Internalization of gp130 seems to be independent from ligand binding [28], and is modulated by phosphorylation at Ser 782 [29] which is located adjacent to the dileucine motif.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“ErbB2 forms a complex with gp130 in an IL-6-dependent manner in prostate carcinoma cells [35].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“In certain cell types, a localization of gp130 in plasma membrane microdomains, such as lipid rafts and caveolae, has been observed [9][10][11].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“After secretion of the CLC-CLF-1 or CLC-CNTFRα complexes, signalling is dependent on CNTFRα and occurs via gp130-LIFR heterodimers.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“Constantinescu et al. [46] identified a hydrophobic motif in the EpoR membrane-proximal domain (Leu 253 , Ile 257 and Trp 258 ) which is conserved in many cytokine receptors and needs to be precisely orientated in order to promote signalling.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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In the paper
“PKCδ enhances the association of STAT3 with the receptor, which possibly involves the phosphorylation of Thr 890 of gp130 [67].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“All IL-6-type cytokines potently activate STAT3, and to a minor extent STAT1 through their common receptor subunit gp130 [4].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
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In the paper
“The Cterminal tyrosine kinase domain is preceded by a pseudokinase domain, which itself is devoid of catalytic activity, but regulates the activity of the kinase domain [3].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“In the cases of LIFR and OSMR, STAT3 and STAT1, as well as STAT5, activation has been observed, with OSMR being the most potent activator of STAT5 [56].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
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In the paper
“These results were confirmed by Chung et al. [105], who also observed that IL-6-induced STAT3 activation is MAPK independent, but sensitive to H7.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Serine phosphorylation
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In the paper
“Cdk9 (cyclin-dependent kinase 9) was also found to bind to gp130, and the association increased upon IL-6 stimulation of HEK 293 cells over-expressing gp130 and Cdk9 [66].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“Deletion of these amino acids reduces IL-6-induced Hck kinase activity, ERK (extracellular-regulated kinase) activation, dephosphorylation of Pyk2 and proliferation of transfected pro-B Ba/F3 cells [65].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“A conformational change in the SH2 domain may account for this dual specificity [91].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
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In the paper
“The recruitment of STATs to the activated receptors has been shown to be mediated by their SH2 domain and requires the phosphorylation of receptor tyrosine motifs [74,[81][82][83].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
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In the paper
“substitution of Trp 652 with alanine (W652A) within the box1 region has no effect on JAK1 association but abrogates JAK1 activation.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mutations with similar consequences (no JAK activation in spite of JAK association) have been described for the EpoR [59], indicating that cytokine receptors in general contribute to the JAK-activation process.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“human fibrosarcoma cells lacking JAK1 express less OSMR at their surface compared with the parental cells, but transient transfection of JAK1 can again increase the amount of surface-expressed receptors [49].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
What the sources say
- Not matchedcites [49]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“Box2 of gp130, a sequence dominated by hydrophobic amino acids followed by charged ones, contributes to JAK binding, presumably by increasing the affinity; a gp130 construct lacking box2 coprecipitates with JAK1 only when the kinase is over-expressed [55].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
What the sources say
- Not matchedcites [55]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“This leads to the formation of active STAT dimers, also shown to be mediated by their SH2 domains [90].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
What the sources say
- Not matchedcites [90]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In response to IL-6, Gab1 is tyrosine phosphorylated and interacts subsequently with SHP2 and PI3K.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A recent study [112] on STAT3 activation in response to EGF (epidermal growth factor) suggests that receptor-mediated endocytosis is required for shuttling of STAT3 from the plasma membrane to the perinuclear region.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [112]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“In the DNA-binding domain of STAT1, initially an NES was postulated that comprises residues 399-410 [108].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [108]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“Compared with the unmethylated protein, methylated STAT1 has a higher tendency to associate with DNA, since its interaction with PIAS (protein inhibitor of activated STATs) 1 (see the subsection below entitled 'PIAS -more than inhibitors of activated STATs?') seems to be weaker [106].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Methylation of STATs
What the sources say
- Not matchedcites [106]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The family of IL-6-type cytokines not only activates ERK1/2, a MAPK known for cellular processes that maintain cell survival, but also the stress-activated members of the MAPK family: p38 and JNK [140-142] (Figure 6).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
What the sources say
- Not matchedcites [140]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [141]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [142]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Sensitivity to leptomycin suggests that nuclear export of STAT1 involves the nuclear export receptor CRM-1 that also acts in a Randependent manner [108,109].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [108]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [109]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“However, from an earlier study [113], it was concluded that nuclear translocation of STAT1 in response to IFNγ does not require cytoskeletal structures, such as actin filaments or microtubules.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [113]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“According to the current view of the SHP2-dependent activation of MAPKs adopted from EGF and PDGF (platelet-derived growth factor) signal transduction, SHP2 links the Grb2-SOS (growthfactor-receptor-bound protein/Son of Sevenless) complex and/or Gab1 (Grb2-associated binder-1) to gp130 [127,129,130].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
What the sources say
- Not matchedcites [127]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [129]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [130]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“In response to IL-2, Epo, EGF, and PDGF, SOCS3 (suppressor of cytokine signalling 3) becomes tyrosine phosphorylated, and subsequently binds and inactivates Ras/GTPase-activating protein.This results in the inhibition of the GTPase activity of Ras, leading to a sustained Ras/GTP and MAPK activity [139].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
What the sources say
- Not matchedcites [139]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“SHP2 is rapidly recruited to tyrosine-phosphorylated gp130 and becomes also phosphorylated in a JAK1-dependent manner [131].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
What the sources say
- Not matchedcites [131]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Dimerization of IL-6-type cytokine receptors does not only lead to activation of the JAK/STAT-signalling pathway, but also to the induction of the MAPK cascade.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Furthermore, nuclear accumulation of constitutively active STAT proteins is independent from endocytosis, because in these cases the STATs are not recruited to any plasma membrane receptor [110,114].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [110]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [114]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“PIAS1 inhibits STAT1 signalling [179], but conversely enhances the transcriptional activity of nuclear hormone receptors [180].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PIAS -more than inhibitors of activated STATs?
What the sources say
- Not matchedcites [179]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [180]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Whereas SHP2 modulates the amount and amplitude of STAT3 activity [131,158], PTPεC affects the kinetics of the onset of STAT3 activation [169].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [131]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [158]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [169]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“It should be noted, however, that PI3K activation upon IL-6 treatment is observed in a cell-type specific manner; e.g.no significant Akt activation could be observed in IL-6treated HepG2 hepatoma cells [149].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of the PI3K cascade: the lipid connection
What the sources say
- Not matchedcites [149]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“This enzyme modifies certain phosphatidylinositides, so that the serine/threonine kinase protein kinase B/Akt is recruited to the plasma membrane, where it becomes activated through phosphorylation by PDK1 (phosphoinositide-dependent kinase-1).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of the PI3K cascade: the lipid connection
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Early results suggested the presence of a nuclear phosphatase which counteracts IFNγ -activated STAT1 and contributes to its nuclear export [121,173].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [121]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [173]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Interaction of SHP2 with JAK1, JAK2 and TYK2, and phosphorylation of SHP2 by JAK1 and JAK2, have at least been shown to occur in vitro [131,162].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [131]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [162]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“IL-6-induced activation of the PI3K/Akt pathway is involved in protection against apoptosis, as well as in enhanced proliferation of multiple myeloma cells [145][146][147].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of the PI3K cascade: the lipid connection
What the sources say
- Not matchedcites [145]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [146]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [147]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“The cytoplasmic variant of PTPε, PTPεC, is expressed in haematopoietic cells and has been shown to selectively inhibit IL-6-induced gp130, JAK and STAT activation [168].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [168]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the other hand, the IL-6induced activation of the MAPK cascade is impaired by mutation of Tyr 759 within gp130, indicating that SHP2, as an adaptor, has a positive function on the activation of the MAPK cascade (as shown in Figure 1).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The family of PIAS comprises five mammalian members: PIAS1, PIAS3, PIASxα, PIASxβ, and PIASy.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PIAS -more than inhibitors of activated STATs?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus methylation not only supports STAT activity (by preventing PIAS association), but also promotes its inactivation by dephosphorylation.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Experiments in vivo underscore the in vitro findings in demonstrating that mice expressing gp130 lacking Tyr 759 display splenomegaly, lymphadenopathy and an enhanced acute-phase reaction [161].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [161]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These differences suggest that signalling components requiring posttranslational modifications for their activation are long-lived, whereas the activity of short-lived proteins is regulated mainly at the transcriptional level.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Half-lives of signalling components: party as long as you live
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Whereas the feedback inhibitors SOCS1, SOCS2 and SOCS3 are very short-lived, STAT1, STAT3α and SHP2 have slow turnover rates.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Half-lives of signalling components: party as long as you live
What the sources say
- Not matchedcites [222]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [223]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The eight members of this family (CIS and SOCS1-SOCS7) contain a central SH2 domain, as well as a C-terminal domain called a SOCS box (Figure 4).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
plainn = 8- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“For gp130, SOCS3 has been found to bind to the phosphotyrosine motif 759 [197,198], which is also the binding site for SHP2.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
What the sources say
- Not matchedcites [197]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [198]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“Phosphorylation occurs at two tyrosine residues (Tyr 204 and Tyr 221 ) within the SOCS box and phosphorylation of Tyr 221 recruits p120 RasGAP leading to sustained ERK activation [139].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
What the sources say
- Not matchedcites [139]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Other reports, however, suggest that elongin C binding can stabilize SOCS1 and that the disruption of the interaction leads to proteasomal degradation of SOCS1 [206,215].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
What the sources say
- Not matchedcites [206]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [215]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Expression of SOCS proteins was found to be rapidly up-regulated by IL-6 (CIS, SOCS1, SOCS2 and SOCS3), LIF (CIS, SOCS1, SOCS2 and SOCS3), IL-11 (SOCS3) and OSM (CIS, SOCS1 and SOCS3) [32,190,192,193].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
What the sources say
- Not matchedcites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [190]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [192]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“As SOCS proteins are induced via the JAK/STAT pathway and subsequently inhibit STAT-mediated signal transduction, they are acting as classical feedback inhibitors.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“These phosphotyrosine residues may be part of an activated receptor or the tyrosine-phosphorylated C-terminal tail of SHP2 (from [156]).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PERSPECTIVES
What the sources say
- Not matchedcites [156]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim have been checked yet.
In the paper
“FKHR specifically enhanced the activity of STAT3-dependent promoters, such as the α 2 M promoter, but not that of a STAT5-responsive promoter.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Other signalling pathways have been shown to induce stabilization of cytokine mRNAs as well: the JNK pathway induces stabilization of the short-lived IL-2 mRNA [219], and PI3K activation induces stabilization of IL-3 mRNA [220].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PERSPECTIVES
What the sources say
- Not matchedcites [219]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [220]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“PI3K activation induces stabilization of IL-3 mRNA [220]”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PERSPECTIVES
What the sources say
- Not matchedcites [220]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“The nuclear receptor co-repressor SMRT (silencing mediator of retinoic and thyroid hormone receptors) is a potential binding partner for STAT5 and represses STAT5-dependent transcription [255].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
What the sources say
- Not matchedcites [255]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“Furthermore, FKHR and STAT3 can be co-immunoprecipitated and co-localize in the nucleus of IL-6-treated HepG2 cells [149].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
What the sources say
- Not matchedcites [149]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“the JNK pathway induces stabilization of the short-lived IL-2 mRNA [219]”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PERSPECTIVES
What the sources say
- Not matchedcites [219]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, an EZI mutant predominantly localized in the cytoplasm inhibited nuclear localization of STAT3, as well as STAT3-mediated transactivation.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Interestingly, Nmi itself is induced by IL-2 and IFNγ , indicating a positive feedback loop within this signal transduction.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
What the sources say
- Not matchedcites [253]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“This interaction is further modulated by Nmi (N-Myc interactor) which augments CBP recruitment to STAT1 and STAT5, and potentiates IL-2 and IFNγ signalling [253].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
What the sources say
- Not matchedcites [253]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The authors state this as an assumption.
The membrane-proximal FNIII domains bridge the ~9 nm distance between the CBM C-termini so that the cytoplasmic parts are close enough to become activated by associated JAKs.
“The membrane-proximal FNIII domains might bridge this distance so that the cytoplasmic parts are in close enough proximity to become activated by the associated JAKs (Figure 5).This assumption is supported by a recent study on the role of the gp130 FNIII domains for heterodimerization with the LIFR [38].”
The paper relies on this without support.
gp130 is ubiquitously expressed.
“Although gp130 is ubiquitously expressed, the number of cells that respond to a certain IL-6-type cytokine is limited, since the expression of the other receptor subunits, especially of the α-receptors, is more restricted and tightly regulated.”
The paper relies on this without support.
IL-6-type cytokines form a subfamily of helix bundle cytokines.
“IL-6-type cytokines form a subfamily of the helix bundle cytokines.”
The paper relies on this without support.
All IL-6-type cytokines comprise four long α-helices A-D arranged in an up-up-down-down topology.
“All IL-6-type cytokines comprise four long α-helices termed A, B, C and D, which are arranged in a way that leads to an up-up-down-down topology (Figure 3).”
The paper relies on this without support.
Each receptor contains at least one cytokine-binding module (CBM) comprising two FNIII domains.
“Each receptor contains at least one cytokine-binding module (CBM) that comprises two FNIII-domains.”
The paper relies on this without support.
JAKs bind to the membrane-proximal region of cytokine receptors, which contains conserved box1 and box2 motifs.
“JAKs bind to the membrane-proximal region of cytokine receptors, which contains conserved so-called box1 and box2 motifs.”
The paper relies on this without support.
The N-terminal region of JAKs comprises a FERM domain crucial for receptor association.
“The N-terminal region of JAKs comprises a FERM (fourpoint-one, ezrin, radixin and moesin) domain which is crucial for receptor association.”
The paper relies on this without support.
The STAT family encompasses seven mammalian members.
“The STAT family of transcription factors encompasses seven mammalian members, designated STAT1, -2, -3, -4, -5a, -5b and -6.”
The paper relies on this without support.
In response to IL-6 stimulation, cytoplasmic STAT3 rapidly accumulates in the nucleus.
“In response to IL-6 stimulation, cytoplasmic STAT3 rapidly accumulates in the nucleus.”
The paper relies on this without support.
Nuclear accumulation is triggered by STAT dimerization in response to tyrosine phosphorylation.
“Nuclear accumulation is triggered by STAT dimerization in response to tyrosine phosphorylation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“IL-6Rα expression is normally associated with hepatocytes and leukocytes but has also been described in cancer cells, including PDAC.”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [40]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The cytokine IL-6 triggers multiple downstream responses, including metabolic regulation.”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [40]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“IL-6, which was discovered in 1986 (27), is a pleiotropic cytokine involved not only in immune responses but also in inflammation, hematopoiesis, bone metabolism, embryonic development and other fundamental processes (1, 21, 28–32).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [30]
Experimental — accuracy not yet measured
Citations
Cites
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Self-citationA family of cytokine-inducible inhibitors of signalling
Starr, R., Willson, T. A., Viney, E. M., Murray, L. J. L., Rayner, J. R., Jenkins, B. J., Gonda, T. J., Alexander, W. S., Metcalf, D., Nicola, N. A., et al. (1997) · Nature · doi:10.1038/43206 · Cited by 2,066
A new protein containing an SH2 domain that inhibits JAK kinases
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Structure and function of a new STAT-induced STAT inhibitor
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Crystal Structure of the Tyrosine Phosphatase SHP-2
Hof, P., Pluskey, S., Dhe‐Paganon, S., Eck, M. J., & Shoelson, S. E. (1998) · Cell · doi:10.1016/s0092-8674(00)80938-1 · Cited by 997
Specific Inhibition of Stat3 Signal Transduction by PIAS3
Chung, C. D., Liao, J., Liu, B., Rao, X., Jay, P., Berta, P., & Shuai, K. (1997) · Science · doi:10.1126/science.278.5344.1803 · Cited by 980
Cited by
Sorted by citations
Items 1,201–1,300 of 3,269
The role of gut microbiota in liver regeneration
Xu, Z., Jiang, N., Xiao, Y., Yuan, K., & Wang, Z. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1003376 · Cited by 41
“The cytoplasmic portion of gp130 dimer associates with JAKs and active the JAK/STAT pathway (31, 32).”
BackgroundKlein, B., Seckinger, A., Moehler, T. M., & Hose, D. (2011) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-540-85772-3_3 · Cited by 38
Davies, R., & Choy, E. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2013.12.002 · Cited by 38
Down-Regulation of miR-3928 Promoted Osteosarcoma Growth
Xu, H., Liu, X., & Zhao, J. (2014) · Cellular Physiology and Biochemistry · doi:10.1159/000358718 · Cited by 37
The STAT3 beacon: IL-6 recurrently activates STAT 3 from endosomal structures
German, C. L., Sauer, B. M., & Howe, C. L. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.05.009 · Cited by 38
“Since OSM utilizes two different combinations of heterodimeric gp130 receptor types [53], unlike IL-6 homodimeric gp130 signaling, residues for STAT3 activation and recruitment may be available on the OSMR/LIFRgp130 receptor complexes that are unavailable upon homodimerized gp130 receptor complexes.”
Trouillas, M., Saucourt, C., Guillotin, B., Gauthereau, X., Ding, L., Buchholz, F., Doss, M. X., Sachinidis, A., Hescheler, J., Hummel, O., et al. (2009) · BMC Genomics · doi:10.1186/1471-2164-10-73 · Cited by 38
“LIF is a member of the Interleukin-6 (IL-6) family of cytokines, which displays pleiotropic functions, depending on both cell maturity and cell type [30-32].”
BackgroundA designer hyper interleukin 11 (H11) is a biologically active cytokine
Dams‐Kozlowska, H., Gryska, K., Kwiatkowska-Borowczyk, E. P., Iżycki, D., Rose‐John, S., & Mackiewicz, A. A. (2012) · BMC Biotechnology · doi:10.1186/1472-6750-12-8 · Cited by 39
“Moreover, soluble forms of the alpha receptors lacking the transmembrane and cytoplasmic domains were found [7].”
BackgroundJAK2 mutants (e.g., JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms
Gäbler, K., Behrmann, I., & Haan, C. (2013) · JAK-STAT · doi:10.4161/jkst.25025 · Cited by 39
Self-citationAngius, A., Uva, P., Buers, I., Oppo, M., Puddu, A., Onano, S., Persico, I., Loi, A., Marcia, L., Höhne, W. E., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.05.026 · Cited by 39
Li, H., Wang, J., Liu, X., & Cheng, Q. (2018) · Biochemistry and Cell Biology · doi:10.1139/bcb-2018-0141 · Cited by 38
Al‐Massri, K. F., Ahmed, L. A., & El-Abhar, H. S. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.12.013 · Cited by 38
“These inflammatory mediators develop neuropathic pain through activation of the Janusactivated kinase–signal transducer and activator of transcription (JAK/ STAT) transduction pathway and activation of mitogen-activated protein kinase (MAPK) pathway [14,15].”
Servais, F., Kirchmeyer, M., Hamdorf, M., Minoungou, N., Rose‐John, S., Kreis, S., Haan, C., & Behrmann, I. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.03.007 · Cited by 37
“Upon phosphorylation, STATs translocate into the nucleus and regulate the expression of various genes, including the one encoding suppressor of cytokine signaling 3 (SOCS3), an important negative regulator of this pathway.(1) Next to this classical signaling pathway triggered by membrane IL6Rgp130 complexes, IL-6 can…”
BackgroundSelf-citationSun, L., Chen, L., Wang, F., Zheng, X., Yuan, C., Niu, Q., Li, Z., Deng, L., Zheng, B., Li, C., et al. (2019) · Gene · doi:10.1016/j.gene.2019.05.033 · Cited by 38
Hepatocyte growth control by SOCS1 and SOCS3
Khan, M. G. M., Ghosh, A., Variya, B. C., Santharam, M. A., Kandhi, R., Ramanathan, S., & Ilangumaran, S. (2019) · Cytokine · doi:10.1016/j.cyto.2019.154733 · Cited by 38
Sanchez, C., Sims, S. G., Nowery, J. D., & Meares, G. P. (2019) · Scientific Reports · doi:10.1038/s41598-019-51481-6 · Cited by 35
Chen, M., Ren, R., Lin, W., Xiang, L., Zhao, Z., & Shao, B. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02260-9 · Cited by 38
“OSM possesses the widest range of downstream signaling pathways among the IL-6 family [2, 17], to name a few, Jak-STAT3, ERK1/ERK2, phosphatidylinositol-3-kinase (PI3K)/Akt, and NF-κB pathways [18–21].”
BackgroundTargeting Systemic Sclerosis from Pathogenic Mechanisms to Clinical Manifestations: Why IL-6?
Cardoneanu, A., Burlui, A., Macovei, L. A., Bratoiu, I., Richter, P., & Rezuş, E. (2022) · Biomedicines · doi:10.3390/biomedicines10020318 · Cited by 39
“A third mechanism of inhibition of IL-6 signaling involves a STAT-3 inhibitor (PIAS3-Protein Inhibitor of Activated STAT 3) that blocks the interaction between phosphorylated STAT3 and cellular DNA and finally genetic transcription [31].”
BackgroundViral Interleukin-6: Structure, pathophysiology and strategies of neutralization
Suthaus, J., Adam, N., Grötzinger, J., Scheller, J., & Rose‐John, S. (2010) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2010.10.016 · Cited by 41
Ng, I. H. W., Yeap, Y. Y. C., Ong, L. S., Jans, D. A., & Bogoyevitch, M. A. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.11.015 · Cited by 38
“One member of the STAT family, STAT3, has attracted attention as a transcription factor mediating the gene expression changes upon stimulation by the interleukin-6 family of cytokines [4].”
BackgroundShen, A., Chen, Y., Hong, F., Lin, J., Wei, L., Hong, Z., Sferra, T. J., & Peng, J. (2012) · Oncology Reports · doi:10.3892/or.2012.2067 · Cited by 38
“The IL-6/sIL-6R complex in turn binds to a common signal transducing receptor gp130, promoting dimerization of gp130 and then resulting in activation of the associated Janus kinases (JAKs).”
InfluentialOncostatin M pathway plays a major role in the renal acute phase response
Luyckx, V. A., Cairo, L. V., Compston, C. A., et al. (2009) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.90633.2008 · Cited by 38
Naimuddin, M., Kobayashi, S., Tsutsui, C., et al. (2011) · Molecular Brain · doi:10.1186/1756-6606-4-2 · Cited by 38
“The activity of IL-6 is exerted through IL-6R [17-19], and IL-6 is known to play a role in the pathogenesis of a variety of diseases such as Rheumatoid arthritis, Castleman’s disease and others [18,20,21].”
BackgroundGolić, N., Veljović, K., Popović, N., Đokić, J., Strahinić, I., Mrvaljević, I., & Terzić-Vidojević, A. (2017) · BMC Microbiology · doi:10.1186/s12866-017-1015-5 · Cited by 40
Cheng, L., Cao, W., Behar, J., Fiocchi, C., Biancani, P., & Harnett, K. M. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.106104 · Cited by 38
“IL-6-type cytokines, via the signal transducers glycoprotein 130, activate the Janus tyrosine kinase/signal transducer and activator of transcription and mitogen-activated protein (MAP) kinase cascades (Heinrich et al., 2003).”
BackgroundCheng, L., Cao, W., Fiocchi, C., Behar, J., Biancani, P., & Harnett, K. M. (2005) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00024.2005 · Cited by 38
Hepcidin Activation During Inflammation: Make It STAT
Fleming, R. E. (2007) · Gastroenterology · doi:10.1053/j.gastro.2006.11.049 · Cited by 36
Campanile, G., Baruselli, P. S., Limone, A., & D’Occhio, M. J. (2021) · Theriogenology · doi:10.1016/j.theriogenology.2021.02.020 · Cited by 39
Extramedullary hematopoiesis in cancer
Barisas, D. A. G., & Choi, K. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01192-4 · Cited by 41
“JAK1 activation leads to the activation of STAT3, MAP kinase pathways, and PI 3 K in amounts that appear to be cell type-speci fi c 187 – 189 .”
BackgroundMicroRNAs, endometrial receptivity and molecular pathways
Salmasi, S., Heidar, M. S., Mahabady, M. K., Rashidi, B., & Mirzaei, H. (2024) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-024-01304-9 · Cited by 41
IL-6 Signaling in Immunopathology: From Basic Biology to Selective Therapeutic Intervention
Schumertl, T., Lokau, J., & Garbers, C. (2025) · ImmunoTargets and Therapy · doi:10.2147/itt.s485684 · Cited by 45
“31,32 Despite these similarities, the functional outcomes of the three signaling modes are fundamentally different.”
Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma
von Felbert, V., Córdoba, F. M., Weissenberger, J., Vallan, C., Kato, M., Nakashima, I., Braathen, L. R., & Weis, J. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)62304-8 · Cited by 37
“18 Two other canonical IL-6-signaling pathways, PI3K/Akt and MAPK, 3,7,48–51 have been characterized thus far.”
BackgroundRamanathan, S., Gagnon, J., & Ilangumaran, S. (2008) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-008-0033-2 · Cited by 41
Liu, J., Xu, X., Feng, X., Zhang, B., & Wang, J. (2011) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-30-80 · Cited by 37
“STAT3 can be activated by IL-6-family cytokines in the classic IL-6/JAK pathway [12,13] and by the growth factors EGF, FGF, and platelet-derived growth factor (PDGF) in target cells expressing receptor tyrosine kinases [14].”
BackgroundCyclic AMP Signaling: A Molecular Determinant of Peripheral Nerve Regeneration
Knott, E. P., Assi, M., & Pearse, D. D. (2014) · BioMed Research International · doi:10.1155/2014/651625 · Cited by 37
“Receptor binding activates the JanusActivated Kinase (JAK) family of tyrosine kinases [15].”
BackgroundBaló-Banga, J. M., Schweitzer, K., Lakatos, S., et al. (2015) · World Allergy Organization Journal · doi:10.1186/1939-4551-8-1 · Cited by 37
Huusko, J. M., Karjalainen, M. K., Mahlman, M., Haataja, R., Kari, M. A., Andersson, S., Toldi, G., Tammela, O. K. T., Rämet, M., Lavoie, P. M., et al. (2014) · BMC Medical Genetics · doi:10.1186/s12881-014-0120-7 · Cited by 37
“Different pathways of IL-6 signaling represent different types of cells that respond to IL-6; this could explain both the pro- and anti-inflammatory actions of IL-6 cytokine [35,36].”
BackgroundAutocrine IL-6 mediates pituitary tumor senescence
Sapochnik, M., Haedo, M. R., Fuertes, M., Ajler, P. M., Carrizo, G., Cervio, A., Sevlever, G. E., Stalla, G. K., & ARZT, E. S. (2016) · Oncotarget · doi:10.18632/oncotarget.13577 · Cited by 41
“There are different IL-6 signaling pathways described [43, 44] that can account for the autocrine and paracrine differential signaling all of which involve STAT3 activation, but also integrate different cross-talk pathways that may explain the differential action on proliferation and senescence.”
BackgroundProgrammed cell senescence: role of IL-6 in the pituitary
Sapochnik, M., Fuertes, M., & ARZT, E. S. (2017) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0026 · Cited by 42
IL6/STAT3 axis mediates resistance to BRAF inhibitors in thyroid carcinoma cells
Notarangelo, T., Sisinni, L., Trino, S., Calice, G., Simeon, V., & Landriscina, M. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.06.038 · Cited by 37
The Emerging Role of Pathogenesis of IgA Nephropathy
Wu, M., Chen, C., Yiang, G., Cheng, P., Chen, Y., Chiu, H.-C., Liu, K., Lee, W., & Li, C. (2018) · Journal of Clinical Medicine · doi:10.3390/jcm7080225 · Cited by 40
“In vitro, IL-6 binding to the IL-6 receptor promotes Janus kinase 2 (JAK2) phosphorylation to activate signal transducer and activator transcription 3 (STAT3), leading to its nuclear translocation (Figure 3) [30].”
BackgroundWang, L., Qiu, J.-G., He, J., Liu, W., Ge, X. Q., Zhou, F.-M., Huang, Y., Jiang, B., & Liu, L.-Z. (2019) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2019.114603 · Cited by 38
“IL-6signals through the common gp130 receptor and the specific IL-6Rα co-receptor to activate the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway and downstream signaling pathways that are involved in tumorigenesis (Heinrich et al., 2003; Heikkila et al., 2008; Pan et al.,…”
BackgroundCrosstalk between myeloid-derived suppressor cells and the immune system in prostate cancer
Sanaei, M., Salimzadeh, L., & Bagheri, N. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.4ru0819-150rr · Cited by 37
Nguyen, A., Zhou, J., Sicairos, B., et al. (2019) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra119.001779 · Cited by 37
“activated by Janus kinases (JAKs) (54).”
Chen, J., Li, X., Huang, C., Lin, Y. H., & Dai, Q.-F. (2020) · Technology in Cancer Research & Treatment · doi:10.1177/1533033820951807 · Cited by 40
Targeting SHP2 as a therapeutic strategy for inflammatory diseases
Liu, Y., Yang, X., Wang, Y., Yang, Y., Sun, D., Li, H., & Chen, L. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113264 · Cited by 40
Interleukin‑6 signalling as a valuable cornerstone for molecular medicine (Review)
Trovato, M. C., Sciacchitano, S., Facciolà, A., Valenti, A., Visalli, G., & Pietro, A. D. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.4940 · Cited by 37
Interleukin 11 (IL-11): Role(s) in Breast Cancer Bone Metastases
Maroni, P., Bendinelli, P., Ferraretto, A., & Lombardi, G. (2021) · Biomedicines · doi:10.3390/biomedicines9060659 · Cited by 39
“The induction of JAK-STAT3 pathway is of particular interest given its role in oncogenesis [47].”
BackgroundSadava, E., Krpata, D., Gao, Y., Rosen, M., & Novitsky, Y. (2014) · Journal of Biomedical Materials Research. Part A · doi:10.1002/jbm.a.34676 · Cited by 34
Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma
Matsunaga, Y., Inoue, H., Fukuyama, S., Yoshida, H., Moriwaki, A., Matsumoto, T., Matsumoto, K., Asai, Y., Kubo, M., Yoshimura, A., et al. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.11.104 · Cited by 37
Williams, J. J. L., Munro, K. M., & Palmer, T. M. (2014) · Cells · doi:10.3390/cells3020546 · Cited by 38
“Tyrosine-phosphorylated STATs can then dimerise and translocate to the nucleus, where they function as transcription factors by binding to specific promoter elements and recruiting transcriptional co-activators [1,2].”
BackgroundInterleukin 6 mediates production of interleukin 10 in metastatic melanoma
Terai, M., Eto, M., Young, G. D., Berd, D., Mastrangelo, M. J., Tamura, Y., Harigaya, K., & Sato, T. (2011) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-011-1084-5 · Cited by 37
“In parallel, the phosphorylation of IL-6R (gp130) and JAKs activates MAP kinases, PI3 kinase/Akt and other cellular pathways through the binding of adaptor proteins [29].”
BackgroundMetcalfe, S. M., Muthukumarana, P., Thompson, H. L., Haendel, M. A., & Lyons, G. E. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.12.027 · Cited by 37
“We speculate that axotrophin may co-operate with SOCS3 in this negative feedback: thus, in the absence of axo- *Level of gene expression at 123 h. **Increase in expression level between 48 and 123 h. trophin, LIF/STAT3 signalling would become dysregulated, revealed by the amplified release of LIF.”
BackgroundInfluentialCell Type-specific Differential Induction of the Human γ-Fibrinogen Promoter by Interleukin-6
Duan, H. O., & Simpson‐Haidaris, P. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600294200 · Cited by 37
Williams, J. J. L., Alotaiq, N., Mullen, W., Burchmore, R., Liu, L., Baillie, G. S., Schaper, F., Pilch, P. F., & Palmer, T. M. (2018) · Nature Communications · doi:10.1038/s41467-017-02585-y · Cited by 35
“Other cytokine receptor complexes that utilise gp130 include those for leukaemia inhibitory factor (LIF) and oncostatin M (OSM): LIF signals via gp130/LIF receptor (LIFR) heterodimers, while OSM signals downstream using either LIFR/gp130 or OSM receptor/ gp130 complexes 41 .”
Self-citationImmunotherapies in chronic pain through modulation of neuroimmune interactions
Zhao, J., Huh, Y., Bortsov, A. V., Diatchenko, L. B., & Ji, R. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108476 · Cited by 42
Role of the interleukin 6 receptor family in epithelial ovarian cancer and its clinical implications
Kumar, J., & Ward, A. C. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2013.12.003 · Cited by 36
Cardó‐Vila, M., Zurita, A. J., Giordano, R. J., Sun, J. D., Rangel, R., Guzman‐Rojas, L., Anobom, C. D., Valente, A. P., Almeida, F. C. L., Lahdenranta, J., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003452 · Cited by 37
“(CNTF), oncostatin-M (OSM), and cardiotrophin-1 (CT-1), IL-11 belongs to the gp130 or IL-6-type [15,16].”
Park, K. W., Nozell, S. E., & Benveniste, E. N. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050874 · Cited by 36
Dominant-negative activity of the STAT3-Y705F mutant depends on the N-terminal domain
Mohr, A., Fahrenkamp, D., Rinis, N., & Müller‐Newen, G. (2013) · Cell Communication and Signaling · doi:10.1186/1478-811x-11-83 · Cited by 35
“IL-6-type cytokines which signal through the cytokine receptor subunit gp130 are among the most potent physiological STAT3 activators [3].”
BackgroundSelf-citationCerbone, A., Toaldo, C., Pizzimenti, S., Pettazzoni, P., Dianzani, C., Minelli, R., Ciamporcero, E. S., Roma, G., Dianzani, M. U., Canaparo, R., et al. (2012) · PPAR Research · doi:10.1155/2012/269751 · Cited by 36
“JAKs phosphorylate gp130, leading to the activation and phosphorylation of the STAT1 and STAT3 transcription factors [22, 23].”
BackgroundLewandowska-Sabat, A. M., Boman, G. M., Downing, A., Talbot, R., Storset, A. K., & Olsaker, I. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-891 · Cited by 37
“It has been shown that phosphorylation of BAD protein and expression of BIRC5mRNA increased cell survival [21,22].”
Quírico‐Santos, T., Meira, I. D., Gomes, A. C., et al. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.08.004 · Cited by 36
“Furthermore, anterior temporal lobe resection and amygdalohippocampectomy was capable to abolish seizures, markedly reduce plasma level of the inflammatory cytokines IL-1β, TNFα, CCL3/ MIP-1α butwithmaintenance of increased IL-6 and TGF-β1 production, both multifunctional cytokines and trophic factors important for pr…”
Moidunny, S., Dias, R. B., Wesseling, E. M., Sekino, Y., Boddeke, H. W. G. M., Sebastião, A. M., & Biber, K. P. H. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06881.x · Cited by 36
Zhou, Z., Bachstetter, A. D., Späni, C. B., Roy, S. M., Watterson, D. M., & Eldik, L. J. V. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0845-2 · Cited by 34
Granulocytes Are Unresponsive to IL-6 Due to an Absence of gp130
Wilkinson, A., Gartlan, K. H., Kelly, G., Samson, L. D., Olver, S. D., Avery, J., Zomerdijk, N., Tey, S., Lee, J. S., Vučković, S., et al. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701191 · Cited by 36
“All IL-6 signaling pathways result in gp130 homodimerization and phosphorylation of STAT3 and STAT1 proteins, which translocate to the nucleus to induce transcriptional modification of target genes (10).”
BackgroundPhosphorylation of LIFR promotes prostate cancer progression by activating the AKT pathway
Shao, J., Zhu, W., Ding, Y., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.02.042 · Cited by 36
Arshad, S., Naveed, M., Ullia, M., Javed, K., Butt, A. J., Khawar, M., & Amjad, F. (2020) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2018-0160 · Cited by 37
“The function of stimulated STAT-3 depends on the transfer of homodimers from underneath the plasma membrane into the nucleus (Heinrich et al., 2003; Liu et al., 2005; Frank, 2007; Herrmann et al., 2007; Lui et al., 2007; Quesnelle et al., 2007; Fletcher et al., 2009).”
BackgroundObesity, Inflammation, and Advanced Prostate Cancer
Rodríguez-Olivas, A. O., & Price, R. S. (2020) · Nutrition and Cancer · doi:10.1080/01635581.2020.1856889 · Cited by 42
“IL-6 is also capable of triggering cellular responses via the MAPK pathway (41).”
BackgroundInfluentialRevisiting IL-6 expression in the tumor microenvironment of classical Hodgkin lymphoma
Gholiha, A. R., Hollander, P., Glimelius, I. C., Hedström, G., Molin, D. L., Hjalgrim, H., Smedby, K. E. E., Hashemi, J., Amini, R., & Enblad, G. (2021) · Blood Advances · doi:10.1182/bloodadvances.2020003664 · Cited by 37
“The IL-6 protein source within IL-6(1) leukocytes and IL-6(1)HRS cells is mainly believed to be from cellular protein synthesis; however, for IL-6(1) HRS cells, paracrine uptake has also been described.(1,35) In tumor tissue, lymphocytes and monocytes secrete IL-6,(1,2,36) whereas healthy plasma cells mostly lack expr…”
ResultCao, Y., Tang, J., Yang, T., Ma, H., Yi, D., Gu, C., & Yu, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055021 · Cited by 36
“reaction by amplifying leukocyte accumulation [16,17].”
Regulation of Suppressor of Cytokine Signaling 3 (SOC3) by Growth Hormone in Pro-B Cells
Barclay, J. L., Anderson, S. T., Waters, M. J., & Curlewis, J. D. (2007) · Molecular Endocrinology · doi:10.1210/me.2006-0498 · Cited by 36
Binding of madindoline A to the extracellular domain of gp130.
Saleh, A. Z., Greenman, K. P., Billings, S. B., Vranken, D. V. V., & Krolewski, J. (2005) · Biochemistry · doi:10.1021/bi050439+ · Cited by 39
Hintzen, C., Evers, C., Lippok, B. E., Volkmer, R., Heinrich, P. C., Radtke, S., & Hermanns, H. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710157200 · Cited by 36
Self-citationThe inflammatory mediator oncostatin M induces stromal derived factor‐1 in human adult cardiac cells
Hohensinner, P. J., Kaun, C., Rychli, K., Niessner, A., Pfaffenberger, S., Rega‐Kaun, G., Fürnkranz, A., Uhrín, P., Zaujec, J., Afonyushkin, T., et al. (2008) · The FASEB Journal · doi:10.1096/fj.08-108035 · Cited by 36
Novotny-Diermayr, V., Lin, B., Gu, L., & Cao, X. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m500175200 · Cited by 40
Macrophage Subset Sensitivity to Endotoxin Tolerisation by Porphyromonas gingivalis
Foey, A., & Crean, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067955 · Cited by 36
IL-6 Is Constitutively Expressed During Lung Morphogenesis and Enhances Fetal Lung Explant Branching
Nogueira‐Silva, C., Santos, M., Baptista, M. J., et al. (2006) · Pediatric Research · doi:10.1203/01.pdr.0000242300.09427.3b · Cited by 36
Lee, Y. J., Heo, J. S., Suh, H. N., Lee, M. Y., & Han, H. J. (2007) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00034.2007 · Cited by 36
“Signal transduction by the IL-6 family of cytokines involves the activation of two major pathways: the JAK/ signal tranducer and activator of transcription (STAT) and MAPK pathways (21).”
BackgroundMelaccio, A., Reale, A., Saltarella, I., Desantis, V., Lamanuzzi, A., Cicco, S., Frassanito, M. A., Vacca, A., & Ria, R. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11216491 · Cited by 38
Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle
Brandt, N., O’Neill, H. M., Kleinert, M., Schjerling, P., Vernet, E., Steinberg, G. R., Richter, E. A., & Jørgensen, S. B. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00313.2014 · Cited by 35
Hsu, H.-J., Yang, Y., Shieh, T., et al. (2014) · The Kaohsiung Journal of Medical Sciences · doi:10.1016/j.kjms.2014.09.003 · Cited by 35
“IL-6 activates mainly the JAK1/STAT3 signal pathway and functions as a proinflammatory factor [15].”
BackgroundHubáčková, S., Krejčíková, K., Bártek, J., & Hodný, Z. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.316869 · Cited by 40
Reily, C., Ueda, H., Huang, Z., Mestecky, J. F., Julian, B. A., Willey, C. D., & Novák, J. (2014) · Journal of Immunology Research · doi:10.1155/2014/197548 · Cited by 36
Sadahira, K., SAGAWA, M., Nakazato, T., Uchida, H., Ikeda, Y., Okamoto, S., Nakajima, H., & Kizaki, M. (2014) · International Journal of Oncology · doi:10.3892/ijo.2014.2652 · Cited by 36
“It is well known that interleukin (IL)-6 plays a critical role in the proliferation of myeloma cells including OPM2 (33).”
BackgroundPutative Role of Serum Amyloid-A and Proinflammatory Cytokines as Biomarkers for Behcet's Disease
Lopalco, G., Lucherini, O. M., Vitale, A., Talarico, R., Lopalco, A., Galeazzi, M., Lapadula, G., Cantarini, L., & Iannone, F. (2015) · Medicine · doi:10.1097/md.0000000000001858 · Cited by 35
“6, 31,32 In addition, it also seems to play a critical role in BD patients presenting with central nervous system involvement, 33 albeit it might have a protective role on mucocutaneous BD features.”
Model-Based Characterization of Inflammatory Gene Expression Patterns of Activated Macrophages
Rex, J., Albrecht, U., Ehlting, C., Thomas, M., Zanger, U. M., Sawodny, O., Häussinger, D., Ederer, M., Feuer, R., & Bode, J. G. (2016) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005018 · Cited by 33
“Briefly, information from the Boolean model regarding activated transcription factors and target genes of the respective pathways as well as the chronology of events is translated into five different input functions for the ODE model representing (u1) genes that are directly regulated via NF-κB upon LPS stimulation, (…”
BackgroundInfluentialZhang, L., Wang, C., Liu, H., et al. (2019) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2019.05.041 · Cited by 35
Induction of Macrophage M2b/c Polarization by Adipose Tissue-Derived Mesenchymal Stem Cells
Sun, M., Sun, L., Huang, C., Chen, B., & Zhou, Z. (2019) · Journal of Immunology Research · doi:10.1155/2019/7059680 · Cited by 33
Kany, S., Janicova, A., & Relja, B. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8111981 · Cited by 39
“Depending on its signaling, IL-6 has pro-inflammatory and anti-inflammatory properties, and plays the central role in activating and maintaining inflammatory responses [95,96].”
BackgroundBiochemical indicators of coronavirus disease 2019 exacerbation and the clinical implications
An, P., Zhu, Y. Z., & Yang, L.-P. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104946 · Cited by 35
“It can activate JAK/STAT, Ras/ERK/C/EBP, and PI3 K/Akt pathways through IL-6R and signal-transducing coreceptor gp130 [78,79].”
Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
Wilmes, S., Jeffrey, P.-A., Martínez‐Fábregas, J., Hafer, M., Fyfe, P. K., Pöhler, E., Gaggero, S., López‐García, M., Lythe, G., Taylor, C., et al. (2021) · eLife · doi:10.7554/elife.66014 · Cited by 35
“…our results suggest that while phosphatases and negative feedback regulators play an important role in maintaining cytokine signaling homeostasis ( Heinrich et al., 2003 ), the kinetics of STAT activation appears to be already encoded at the level of receptor engagement, thus ensuring maximal…”
BackgroundThe Molecular Culprits Underlying Precocious Mammary Gland Involution
Sutherland, K. D., Lindeman, G. J., & Visvader, J. E. (2007) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-007-9034-8 · Cited by 34
“Oncostatin M (OSM) signals though a heterodimeric complex composed of the OSM-specific β subunit and gp130 [24] and results in the activation of both the JAK/STAT and MAP kinase signal transduction pathways.”
BackgroundThyrell, L., Arulampalam, V., Hjortsberg, L., Farnebo, M., Grandér, D., & Tamm, K. P. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.08.007 · Cited by 37
Minimal role for STAT1 in interleukin‐6 signaling and actions in the murine brain
Sanz, E., Hofer, M. J., Unzeta, M., & Campbell, I. L. (2007) · Glia · doi:10.1002/glia.20602 · Cited by 35
“Cellular communication by IL-6 is mediated at the surface of the cell by the binding of IL-6 to the IL-6 receptor (IL-6R), which triggers the recruitment of the signal transducer subunit gp130 (for review see Heinrich et al., 2003).”
BackgroundChoi, J. H., Kim, H. S., Kim, S.-H., Yang, Y. R., Bae, Y. S., Chang, J., Kwon, H. M., Ryu, S. H., & Suh, P. (2006) · Nature Cell Biology · doi:10.1038/ncb1509 · Cited by 35
Perspective: Expanding role of cyclin dependent kinases in cytokine inducible gene expression
Brasier, A. R. (2008) · Cell Cycle · doi:10.4161/cc.7.17.6594 · Cited by 35
Therapeutic potential of LIF in multiple sclerosis
Slaets, H., Hendriks, J. J. A., Stinissen, P., Kilpatrick, T. J., & Hellings, N. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.08.007 · Cited by 37
What the semantic web could do for the life sciences
Neumann, E., Miller, E., & WILBANKS, J. T. (2004) · Drug Discovery Today BIOSILICO · doi:10.1016/s1741-8364(04)02420-5 · Cited by 35
Mazur, B., Mertas, A., Sońta-Jakimczyk, D., et al. (2004) · Hematological Oncology · doi:10.1002/hon.725 · Cited by 35
Tying the knot between cytokine and toll‐like receptor signaling in gastrointestinal tract cancers
Tye, H., & Jenkins, B. J. (2013) · Cancer Science · doi:10.1111/cas.12205 · Cited by 35
Metadata
- Authors
- HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Institut für Biochemie, RWTH Aachen, Universitätsklinikum, Pauwelsstrasse 30, D-52074 Aachen, Germany
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2003-08-15
- Volume
- 374
- Issue
- 1
- Pages
- 1-20
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1223585
- OpenAlex
- W2086840459
- Cited by
- 3,272
- References
- 265
- Citations by year
- 2026: 70 · 2025: 114 · 2024: 106 · 2023: 121 · 2022: 138 · 2021: 146 · 2020: 129 · 2019: 151 · 2018: 141 · 2017: 141 · 2016: 176 · 2015: 157 · 2014: 171 · 2013: 190 · 2012: 179
- FWCI
- 50.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- cytokine signaling, gp130, LIF receptor, OSM receptor, JAK/STAT signaling, MAPK signaling, protein tyrosine phosphatase, suppressor of cytokine signaling, PIAS, signal termination, signal transduction, acute phase response, inflammation, rheumatoid arthritis, multiple myeloma, prostate cancer
- MeSH terms
- Animals, Humans, Infections, Models, Molecular, Phosphorylation, Protein Conformation, Wounds and Injuries, Signal Transduction, Interleukin-6, Cytokines, Protein Structure, Secondary, Receptors, Interleukin-6
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