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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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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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In the paper
“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 the paper
“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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“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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- Not matchedcites [45]
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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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- Not matchedcites [55]
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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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- Not matchedcites [59]
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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
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- Not matchedcites [49]
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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.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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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
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Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
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Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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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
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- Not matchedcites [108]
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- 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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?
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Strength:plain· not yet calibratedn = 8Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.”
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“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
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Batf Promotes Growth Arrest and Terminal Differentiation of Mouse Myeloid Leukemia Cells
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“M1 cells proliferate as a transformed blast cell population until exposed to a member of the IL-6/LIF family of cytokines (17-19), at which point the cells exit the cell cycle and initiate a program duplicating many aspects of monocyte to”
BackgroundWinship, A., Correia, J., Krishnan, T., et al. (2015) · Scientific Reports · doi:10.1038/srep13237 · Cited by 35
“…and is a secreted glycoprotein that signals via the gp130/LIF receptor (LIFR α ) complex to activate downstream signaling cascade including the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) 6–10 and extracellular signal-regulated kinase (ERK) 11 pathways.”
InfluentialMakki, M. S., & Haqqi, T. M. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2016.06.010 · Cited by 35
“We did not study the signaling events in the present study but it is known that IL-6 signals through activation of both STAT and mitogen-activated protein kinase pathways.(36,20) Specific inhibitors of the STAT pathway block MMP production in IL-6estimulated chondrocytes.”
BackgroundInfluentialBöing, I., Stroß, C., Radtke, S., Lippok, B. E., Heinrich, P. C., & Hermanns, H. M. (2005) · Cellular Signalling · doi:10.1016/j.cellsig.2005.03.015 · Cited by 36
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“The literature on the IL-6 functions on cancers reports that IL-6 binds to its receptor (IL-6R) and forms a complex with glycoprotein 130 (IL6Rβ) to activate the downstream protein kinases, and subsequently activates STAT1, 3, and 5 (Heinrich et al., 2003; Babon et al., 2014; Jones and Jenkins, 2018) contributing to p…”
BackgroundNerstedt, A., Cansby, E., Amrutkar, M., Smith, U., & Mahlapuu, M. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.05.013 · Cited by 36
“However, in our study no difference in total protein level of JAK1/2 was observed, excluding the role of proteases in deactivation of JAKs in response to AMPK activation.”
BackgroundInfluentialCytokine profiles in sickle cell anemia: Pathways to be unraveled
Pitanga, T. N., Vilas-Boas, W., Cerqueira, B. A. V., Seixas, M. O., Barbosa, C. G., Adôrno, E. V., & Gonçalves, M. D. S. (2013) · Advances in Bioscience and Biotechnology · doi:10.4236/abb.2013.47a1002 · Cited by 34
“These cytokines are defined by their common usage of the widely expressed signal-transducing b subunit of the transmembrane receptor glycoprotein 130 (gp 130), which is a member of the class of type I cytokine receptors [19,20].”
Matrix Remodeling Maintains Embryonic Stem Cell Self-Renewal by Activating Stat3
Przybyla, L., Theunissen, T. W., Jaenisch, R., & Joel Voldman, B. (2013) · Stem Cells · doi:10.1002/stem.1360 · Cited by 34
STAT3 as a therapeutic target for Epstein-Barr virus (EBV) – associated nasopharyngeal carcinoma
Ho, Y., Tsao, S., Zeng, M., & Lui, V. W. Y. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.11.052 · Cited by 36
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Methylation status of interleukin-6 gene promoter in patients with Behçet's disease
Alipour, S., Sakhinia, E., Khabbazi, A., Samadi, N., Babaloo, Z., Azad, M., Abolhasani, S., Farhadi, J., Jadideslam, G., Roshanravan, N., et al. (2018) · Reumatología Clínica · doi:10.1016/j.reuma.2018.06.006 · Cited by 36
Decoding the enigma of antiviral crisis: Does one target molecule regulate all?
Mahmud-Al-Rafat, A., Majumder, A., Rahman, K. M. T., Hasan, A. M. M., Islam, K. M. D., Taylor-Robinson, A. W., & Billah, M. M. (2019) · Cytokine · doi:10.1016/j.cyto.2018.12.008 · Cited by 34
Cytokine storm and targeted therapy in hemophagocytic lymphohistiocytosis
Zhang, H., Yang, S., Fu, Y., Chen, M.-C., Yang, C.-H., Yang, M., Liu, X.-D., He, Q., Jiang, H., & Zhao, M. (2022) · Immunologic Research · doi:10.1007/s12026-022-09285-w · Cited by 35
“In the JAK-STAT3 pathway, STAT3 is phosphorylated by JAK kinase to form a homologous dimer that is transferred to the nucleus for transcriptional activity [39].”
BackgroundTransformation of human bronchial epithelial cells alters responsiveness to inflammatory cytokines
Loewen, G., Tracy, E., Blanchard, F., et al. (2005) · BMC Cancer · doi:10.1186/1471-2407-5-145 · Cited by 34
“The signaling proteins are recruited to the tyrosine phosphorylated receptors, include signal transducer and activator of transcription-3 (STAT3), the protein tyrosine phosphatase SHP-2 and the adaptor Shc, which link to the RAS-MAPK-ERK pathway [14,15].”
BackgroundInfluentialPallotta, M. T., Orabona, C., Volpi, C., Grohmann, U., Puccetti, P., & Fallarino, F. (2010) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s3971 · Cited by 34
Jawa, R. S., Chattopadhyay, S., Tracy, E., et al. (2008) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2007.0057 · Cited by 34
Takata, F., Sumi, N., Nishioku, T., Harada, E., Wakigawa, T., Shuto, H., Yamauchi, A., & Kataoka, Y. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.06.030 · Cited by 34
Cardiotrophin-1 Maintains the Undifferentiated State in Skeletal Myoblasts
Miyake, T., Alli, N. S., Aziz, A., Knudson, J., Fernando, P., Megeney, L. A., & McDermott, J. C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.017319 · Cited by 34
Recombinant Interleukin-24 Lacks Apoptosis-Inducing Properties in Melanoma Cells
Kreis, S., Philippidou, D., Margue, C., Rolvering, C., Haan, C., Dumoutier, L., Renauld, J., & Behrmann, I. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001300 · Cited by 34
Self-citationProinflammatory Homeobox Gene, ISX , Regulates Tumor Growth and Survival in Hepatocellular Carcinoma
Hsu, S., Wang, L., Lee, K.-T., Chen, Y.-L., Liu, K.-Y., Suen, J., Chai, C., & Wang, S. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2795 · Cited by 33
“IL6 activatesmany signaling pathways to transform cellular responses, including JAK/STATs, MAPK, and AKT/PI3K (17, 31), and, through activating JAK/STAT3 signaling, NF-kB and downstream genes, such as Isx, are consequently activated to mediate cell survival and G1 to S cell-cycle transition.”
BackgroundCollagenase gene regulation by pro-inflammatory cytokines in cartilage
Andrew, D. R. (2006) · Frontiers in bioscience · doi:10.2741/2080 · Cited by 34
The Regenerative Activity of Interleukin-6
Galun, E., & Rose-John, S. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-308-4_4 · Cited by 34
Vergne‐Salle, P., Leger, D. Y., Bertin, P., et al. (2005) · Cytokine · doi:10.1016/j.cyto.2005.06.002 · Cited by 34
Laflamme, J., Akoum, A., & Leclerc, P. (2005) · Molecular Human Reproduction · doi:10.1093/molehr/gah142 · Cited by 36
“This signal transducer is also known as the b-subunit of the IL-6 receptor and also acts as a subunit of the receptor for other cytokines such as LIF, oncostatin, IL-11 and CNTF (Lutticken et al., 1994; Stahl et al., 1994; Heinrich et al., 2003).”
BackgroundResultInfluentialMaking sense of IL‐6 signalling cues in pathophysiology
Millrine, D., Jenkins, R. L., Hughes, S. T. O., & Jones, S. A. (2021) · FEBS Letters · doi:10.1002/1873-3468.14201 · Cited by 39
“The signalling pathways associated with IL-6 signalling are discussed at length in the literature [1,4,31,32].”
BackgroundInfluentialDissook, S., Umsumarng, S., Mapoung, S., Semmarath, W., Arjsri, P., Srisawad, K., & Limtrakul, P. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2022.1072056 · Cited by 33
“From the molecular biology of inflammation perspective, IL-6 cytokine has mostly been recognized for being involved in cytokine receptors and the JAKs/STATs signaling pathway (55).”
BackgroundSTAT3: a critical component in the response toHelicobacter pyloriinfection
Menheniott, T. R., Judd, L. M., & Giraud, A. S. (2015) · Cellular Microbiology · doi:10.1111/cmi.12518 · Cited by 34
“Subsequently, gp130 is activated by phosphorylation; associated JAK kinases are also phosphorylated, as is STAT3 (pTyr705). pSTAT3 dissociates, dimerises and moves to the nucleus to initiate target gene transcription (Heinrich et al., 2003; Wake and Watson, 2015).”
BackgroundCytokinome profile evaluation in patients with hepatitis C virus infection.
Capone, F., Guerriero, E., Colonna, G., Maio, P., Mangia, A., Castello, G., & Costantini, S. (2014) · PubMed Central · doi:10.3748/wjg.v20.i28.9261 · Cited by 33
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“IL-6 can promote tumorigenic conversion of oncogene-immortalized benign cells through STAT3-mediated trans-activating other cellular signaling pathways, such as MAPK, PI3K/AKT, and insulin-like growth factor I receptor (IGF-IR) signaling axis [14, 20].”
BackgroundWu, C., Ge, J., Yang, M., Yan, Q., Wang, Y., Yu, H., Yang, H., & Zou, J. (2021) · European journal of medical research · doi:10.1186/s40001-021-00555-1 · Cited by 35
“These aforementioned cytokines are mainly involved in activating target genes responsible for cell differentiation, survival, proliferation, and apoptosis (19).”
BackgroundEndosomes as Signaling Platforms for IL-6 Family Cytokine Receptors
Schmidt‐Arras, D., & Rose‐John, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.688314 · Cited by 33
Ling, H.-Y., Yang, Z. H., Wang, P., Sun, Y., Ju, S.-G., Li, J., & Fu, J. X. (2021) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2021.109779 · Cited by 33
Maier, E., Mittermeir, M., Ess, S., Neuper, T., Schmiedlechner, A., Duschl, A., & Horejs‐Hoeck, J. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.661306 · Cited by 31
“Engagement of gp130 typically activates the transcription factors STAT1, STAT3, and STAT5, but it can also activate MAPK signaling and the PI3K/Akt pathway (2).”
BackgroundGraf, D., Kohlmann, C., Haselow, K., Gehrmann, T., Bode, J. G., & Häussinger, D. (2006) · Hepatology · doi:10.1002/hep.21368 · Cited by 32
“This is supported by several observations: (1) apart from hydrophobic bile acids, other caspase-activating stimuli such as addition of CD95 ligand or hyperosmotic exposure induced gp130 downregulation; (2) GDCD-induced gp130 downregulation was sensitive to caspase-3 or -8 inhibitors and to the antiapoptotic bile acid…”
ResultCold-induced sweating syndrome A report of two cases and demonstration of genetic heterogeneity
Hahn, A. F., Jones, D. L., Knappskog, P. M., Boman, H., & McLeod, J. G. (2006) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2006.07.001 · Cited by 33
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Towards a new age in the treatment of multiple myeloma
Piazza, F., Gurrieri, C., Trentin, L., & Semenzato, G. (2007) · Annals of Hematology · doi:10.1007/s00277-006-0239-5 · Cited by 32
“IL-6 stimulates proliferation [38], survival [39], and resistance to drugs [40] of MM cells.”
Moon, C., Liu, B. Q., Kim, S. Y., et al. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21919 · Cited by 33
“Although several growth factors participate in this process (Taga and Kishimoto, 1997; Heinrich et al., 1998, 2003; Huang and Reichardt, 2001), information about the growth factors that maintain these cells in an immature state and control terminal differentiation is limited.”
BackgroundVlotides, G., Zitzmann, K., Stalla, G. K., & Auernhammer, C. J. (2004) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2004.04.002 · Cited by 33
Park, Y. D., Jin, C. H., Choi, D. S., et al. (2011) · Archives of Pharmacal Research · doi:10.1007/s12272-011-0806-8 · Cited by 33
“The pro-inflammatory cytokine, IL-6, as well as proinflammatory mediators, NO and MCP-1, play important roles in the inflammatory process (Heinrich et al., 2003; Melgarejo et al., 2009).”
BackgroundCardiotrophin-1 reduces ischemia/reperfusion injury during liver transplant
Aguilar‐Melero, P., Luque, A., Machuca, M. M. G., et al. (2012) · Journal of Surgical Research · doi:10.1016/j.jss.2012.07.046 · Cited by 33
“[7] Heinrich PC, Behrmann I, Haan S, Hermanns HM, MullerNewen G, Schaper F.”
BackgroundThe acute-phase response of the liver in relation to thyroid hormone-induced redox signaling
Tapia, G., Fernández, V., Pino, C. J., et al. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.12.033 · Cited by 33
“5) [17,30,34].”
JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?
Smirnova, О. V., Ostroukhova, T. Y., & Bogorad, R. L. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.13.6478 · Cited by 33
Therapeutic Inhibition of Jak Activity Inhibits Progression of Gastrointestinal Tumors in Mice
Stuart, E., Büchert, M., Putoczki, T. L., Thiem, S., Farid, R., Elzer, J., Huszar, D., Waring, P., Phesse, T. J., & Ernst, M. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0583-t · Cited by 32
“Upon ligand engagement of the receptor, the GP130-associated Janus kinases (JAK) JAK1, JAK2, and TYK2 undergo activation before recruiting and phosphorylating cytoplasmic STAT3 to promote its dimerization, nuclear translocation, and transcriptional activity (4).”
Cho, N., Nguyen, D. H., Satkunendrarajah, K., Branch, D. R., & Fehlings, M. G. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-134 · Cited by 33
“subunit then recruits the signaling gp130 receptor subunit [27].”
BackgroundYe, L., Mou, Y., Wang, J., & Jin, M. (2017) · Oncotarget · doi:10.18632/oncotarget.17258 · Cited by 33
RetractedLi, Y., Hsieh, L., Tang, R., Liao, S.-K., & Yeh, K. (2009) · Cellular Immunology · doi:10.1016/j.cellimm.2009.01.001 · Cited by 33
“Interleukin-6 (IL-6) binds to a hexametric receptor, composed of an IL-6 receptor alpha chain (IL-6Ra) and a signal transducer, gp130, and the interaction of IL-6 and its receptor subsequently induces tyrosine phosphorylation (Tyr) of STAT3 proteins that bind directly to target genes [1–3].”
BackgroundTranscriptional Activity of the ΔNp63 Promoter Is Regulated by STAT3
Chu, W., Dai, P., Li, H., & Chen, J.-K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800183200 · Cited by 33
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Inflammation accelerating intestinal fibrosis: from mechanism to clinic
Xin, S., Liu, X., He, C., Gao, H., Wang, B., Hua, R., Gao, L., Shang, H., Sun, F., & Xu, J. (2024) · European journal of medical research · doi:10.1186/s40001-024-01932-2 · Cited by 36
“IL-6 activates the JAK/STAT and MAPK cascades, which preserve mucosal integrity via the gp130, LIF, and OSM receptors [128, 131] as more details depicted in Fig.”
BackgroundTrubiani, O., Cataldi, A., Angelis, F. D., et al. (2011) · International Endodontic Journal · doi:10.1111/j.1365-2591.2011.01942.x · Cited by 32
Simvastatin Protects Against T Cell Immune Dysfunction in Abdominal Sepsis
Zhang, S., Luo, L., Wang, Y., Rahman, M., Lepsenyi, M., Syk, I., Jeppsson, B. W., & Thorlacius, H. (2012) · Shock · doi:10.1097/shk.0b013e31826fb073 · Cited by 32
“Interleukin 6 is a complex cytokine exerting both proinflammatory and anti- inflammatory effects (37), which may be related to different signaling pathways of IL-6 (38, 39).”
BackgroundInfluentialStec, W. J., & Zeidler, M. P. (2011) · Journal of Signal Transduction · doi:10.1155/2011/894510 · Cited by 32
“Wing venation requires JAK/STAT and EGFR/MAPK signalling pathways, that have been frequently found to crosstalk in mammals [32, 54–58].”
BackgroundObesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling
Gruber, S. G., Straub, B. K., Ackermann, P., Wunderlich, C. M., Mauer, J., Seeger, J. M., Büning, H., Heukamp, L. C., Kashkar, H., Schirmacher, P., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.07.023 · Cited by 33
“…by binding to the IL-6R consisting of two subunits of the signal-transducing b chain of the receptor that is also used by a cohort of other IL-6-type cytokines and one subunit of the IL-6Ra chain that confers IL-6 binding and thus specificity to the receptor complex (Heinrich et al., 2003).”
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Yang, X., Lin, A., Jiang, N., et al. (2016) · Nephrology · doi:10.1111/nep.12746 · Cited by 32
“The active gp130 triggers a complex intracellular cascade involving STAT factor, JAK andMAPKand results in increased transcription of some critical genes.(27) In the transsignalling pathway, IL-6 binds to a soluble form of IL-6R (sIL-6R) produced by splicing or proteolytic cleavage of IL-6R,(9,28) enabling the activat…”
BackgroundKattner, A.-S., Holler, E., Holler, B., et al. (2020) · Annals of Hematology · doi:10.1007/s00277-020-03968-w · Cited by 32
Magidey, K., Cooper, T. J., Kveler, K., Normand, R., Zhang, T., Timaner, M., Raviv, Z., James, B. P., Gazit, R., Ronai, Z. A., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002856 · Cited by 34
Investigation of IL-6 and IL-10 signalling via mathematical modelling
Moya, C., Huang, Z. J., Cheng, P., Jayaraman, A., & Hahn, J. (2011) · IET Systems Biology · doi:10.1049/iet-syb.2009.0060 · Cited by 32
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Cytokines and sudden infant death
Vennemann, M. M., Loddenkötter, B., Fracasso, T., et al. (2011) · International Journal of Legal Medicine · doi:10.1007/s00414-011-0638-6 · Cited by 32
“In acute inflammation, soluble IL-6 receptor increases and limits the accumulation of neutrophil granulocytes as well as the immigration of CD3+ T lymphocytes [7].”
BackgroundInflammatory Consequences of Lung Ischemia-Reperfusion Injury and Low-Pressure Ventilation
Cobelens, P. M., van Putte, B. P., Kavelaars, A., et al. (2008) · Journal of Surgical Research · doi:10.1016/j.jss.2008.04.022 · Cited by 32
Cytokines that promote nerve regeneration
Zigmond, R. E. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.08.017 · Cited by 34
“dimerization of the factor and its translocation to the cell nucleus, and activation of a set of responsive genes (Heinrich et al., 2003).”
BackgroundInfluentialTRIM8 regulates Nanog via Hsp90β-mediated nuclear translocation of STAT3 in embryonic stem cells
Okumura, F., Okumura, A. J., Matsumoto, M., Nakayama, K. I., & Hatakeyama, S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.05.013 · Cited by 32
“Since many cytokine receptors do not have intrinsic tyrosine-kinase activity, ligand engagement leads to the activation of receptor-associated tyrosine kinases, which are usually members of the JAK family [23–26].”
BackgroundZhang, L., Zhang, B., & Hu, Y. (2014) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2014.05.026 · Cited by 32
Gabexate Mesilate Inhibits the Expression of HMGB1 in Lipopolysaccharide-Induced Acute Lung Injury
Hidaka, S., Iwasaka, H., Hagiwara, S., et al. (2009) · Journal of Surgical Research · doi:10.1016/j.jss.2009.05.039 · Cited by 32
The role of aldosterone in mediating the dependence of angiotensin hypertension on IL-6
Sturgis, L. C., Cannon, J. G., Schreihofer, D. A., & Brands, M. W. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90995.2008 · Cited by 33
Prevention of Colitis-associated Cancer: Natural Compounds that Target the IL-6 Soluble Receptor
Moriasi, C. M., Subramaniam, D., Awasthi, S., Ramalingam, S., & Anant, S. (2012) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152012803833080 · Cited by 32
Interleukin-6 Trans-Signaling and Colonic Cancer Associated with Inflammatory Bowel Disease
Chalaris, A., Schmidt‐Arras, D., Yamamoto, K., & Rose‐John, S. (2012) · Digestive Diseases · doi:10.1159/000341698 · Cited by 33
Metodieva, S., Nikolova, D. N., Cherneva, R. V., Dimova, I. I., Petrov, D., & Toncheva, D. I. (2011) · Tumori Journal · doi:10.1177/030089161109700116 · Cited by 32
IL-6 and type 1 diabetes mellitus: T cell responses and increase in IL-6 receptor surface expression
Gomes, K. B. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2016.12.74 · Cited by 32
“Subsequently, STAT proteins (STAT1 and STAT3) are phosphorylated, dimerize, and translocate to the nucleus, where they induce transcription of target genes (6,7).”
BackgroundLim, H. J., Jang, H. J., Bak, S. G., et al. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.04.053 · Cited by 32
Bongartz, H., Gille, K., Hessenkemper, W., Mandel, K., Lewitzky, M., Feller, S., & Schaper, F. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0451-2 · Cited by 28
Self-citationNeuropoietin Attenuates Adipogenesis and Induces Insulin Resistance in Adipocytes
White, U. A., Stewart, W. C., Mynatt, R. L., & Stephens, J. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710462200 · Cited by 32
Protective Effect and Mechanism of Placenta Extract on Liver
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“Binding of IL-6 to its receptor, IL-6R, activates the JAK kinase family (JAK1, JAK2, and TYK2) (99).”
BackgroundJohnston, P. A., Sen, M., Hua, Y., et al. (2013) · Assay and Drug Development Technologies · doi:10.1089/adt.2013.524 · Cited by 31
“Reciprocal interactions between SH-2 domains of pSTAT3 monomers and the pY705 residue of another pSTAT3 partner lead to dimerization and translocation into the nucleus, where pSTAT3 dimers bind specific DNA response elements in the promoters of target genes to regulate transcription.(2,4,5,8,12,13) STAT3 target genes…”
InfluentialXiong, B., & Huinan, Q. (2013) · 中医杂志：英文版 · doi:10.1016/s0254-6272(13)60105-3 · Cited by 31
The Immunopathology of Cutaneous Lupus Erythematosus
Kirchhof, M. G., & Dutz, J. P. (2014) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2014.04.006 · Cited by 30
Oncostatin M and leukemia inhibitory factor increase hepcidin expression in hepatoma cell lines
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“LIFR and OSMR are known to activate STAT3 and STAT5 [17].”
BackgroundInfluentialEleje, G. U., Ezugwu, E. C., Eke, A. C., et al. (2017) · Journal of Perinatal Medicine · doi:10.1515/jpm-2016-0339 · Cited by 31
Involvement of STAT1 in proliferation and invasiveness of trophoblastic cells
de Sousa, F. L. P., Chaiwangyen, W., Prieto, D. M. M., et al. (2017) · Reproductive Biology · doi:10.1016/j.repbio.2017.05.005 · Cited by 31
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Chao, C., Akileswaran, L., Bailey, J. N. C., et al. (2018) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.18-24845 · Cited by 31
“IL-6 is a pleotropic mediator with both pro- and antiinflammatory properties.(54,55) It has been shown to be directly involved in both the defense and homeostatic maintenance of the ocular surface.”
BackgroundDawidowska, M., Jaksik, R., Drobna‐Śledzińska, M., Szarzyńska‐Zawadzka, B., Kosmalska, M., Sędek, Ł., Machowska, L., Lalik, A., Lejman, M., Ussowicz, M., et al. (2019) · Neoplasia · doi:10.1016/j.neo.2019.01.004 · Cited by 32
“Binding of IL6 to its receptor triggers JAK/STAT signaling, with the final activation of STAT3 transcription factor and subsequent expression of its target genes [71].”
BackgroundLiu, Z., Wang, H., Guan, L., Lai, C., Yu, W., & Lai, M. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14863 · Cited by 32
“The STATs are latent cytoplasmic transcription factors which can be activated by extracellular signalling ligands such as cytokines, growth factors, and hormones (Catlett‐Falcone et al., 1999; Darnell, Kerr, & Stark, 1994; Heinrich et al., 2003; Stark, Kerr, Williams, Silverman, & Schreiber, 1998; Zhong, Wen, & Darnel…”
BackgroundBalancing STAT Activity as a Therapeutic Strategy
Polak, K. L., Chernosky, N. M., Smigiel, J. M., Tamagno, I., & Jackson, M. W. (2019) · Cancers · doi:10.3390/cancers11111716 · Cited by 30
“In addition, side effects of JAK inhibitors may be more pronounced, as JAKs activate other pathways, such as MAPK and PI3K in normal cells as well as cancer [43].”
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Hosseini, A., Gharibi, T., Mohammadzadeh, A., et al. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119395 · Cited by 31
T cells in ocular autoimmune uveitis: Pathways and therapeutic approaches
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“The IL-6 family of cytokines signal via the activation of JAK (Janus kinase) tyrosine kinases, leading to the activation of STAT (signal transducers and activators of transcription) transcription factors, which regulate a range of target genes (4).”
Backgroundda Rocha, L. F., Rêgo, M. J. B. D. M., Cavalcanti, M. B., Pereira, M. C., Pitta, M. G. D. R., de Oliveira, P. S. S., Gonçalves, S. M. C., Duarte, Â. L. B. P., de Lima, M. D. C. A., Pitta, I. D. R., et al. (2013) · BioMed Research International · doi:10.1155/2013/926060 · Cited by 33
“Another very interesting TM17 result is the reduction of IL-6 which participates in the Th17 phenotype polarization [26], suggesting that IL-6 secretion inhibition by TM17 could be associated with IL-17A reduced levels.”
Frontal-Subcortical Protein Expression following Prenatal Exposure to Maternal Inflammation
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“Activation of JAK/STAT pathway is particularly important in neuronal regeneration, embryonic development [37], neurogensis and gliogensis [38].”
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“A cytometric bead array (BD Biosciences) was used to measure IL-8 and IL-6, produced in the cocultures.”
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“IL-6 signals through STAT1 and STAT3, suggesting that perhaps IL-6 shares similar signaling pathways with other inhibitors of OCP differentiation [51].”
Background
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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