Principles of interleukin (IL)-6-type cytokine signalling and its regulation

Human OSM forms both LIFR-gp130 and OSMR-gp130 heterodimers.

“Human OSM has the exceptional capability to recruit two different receptor complexes.It forms both LIFR-gp130 and OSMR-gp130 heterodimers.”

• cites [4]Not matched

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LIF and OSM directly engage their signalling receptor subunits without requirement for additional α-receptor subunits.

“LIF and OSM directly engage their signalling receptor subunits without requirement for additional α-receptor subunits (Figure 2) [4,6].”

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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.

“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].”

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sIL-6Rα potentiates the antagonistic activity of sgp130.

“It has been demonstrated that sIL-6Rα potentiates the antagonistic activity of sgp130.”

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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.

“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].”

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The minimal requirement for gp130 receptor activation is one intact antibody and the Fab of the second antibody.

“The minimal requirement for receptor activation is one intact antibody and the Fab (fragment antigen binding) of the second antibody.”

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The membrane-proximal FNIII domains of signalling receptors are necessary for coupling ligand binding and signal transduction, since deletion of these domains leads to signalling incompetent receptors.

“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].”

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In the gp130 homodimer, two different binding epitopes of gp130 are involved in ligand recognition.

“Thus in the homodimer two different binding epitopes of gp130 are involved in ligand recognition [23].”

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The interaction sites predicted by mutagenesis studies have 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.

“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].”

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In contrast with α-receptors, the receptors that initiate signal transduction have three additional membrane-proximal FNIII domains.

“In contrast with the α-receptors, the receptors that initiate signal transduction have three additional membrane-proximal FNIII domains [4].”

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To become secreted, CLC must be coexpressed with either CLF-1 or CNTFRα.

“To become secreted, CLC must be coexpressed with either CLF-1 (cytokine-like factor-1) or CNTFRα.”

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Site III is recognized by the Ig-like domain of gp130, LIFR or OSMR.

“A surprise was the discovery that site III is recognized by the Ig-like domain of gp130, LIFR or OSMR [19][20][21][22].”

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Insertion of one to four alanine residues into the membrane-proximal intracellular region of gp130 demonstrated that full activation of the receptor was only obtained with the wild-type and the +3A-mutant.

“Interestingly, insertion of one to four alanine residues into the membrane-proximal intracellular region of gp130 demonstrated that full activation of the receptor (i.e.induction of target genes) was only obtained with the wild-type and the + 3A-mutant [45].”

• cites [45]Not matched

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Efficient gp130 activation could not be achieved by a single antibody, but requires the action of two distinct monoclonal antibodies.

“Unlike many other receptors, efficient gp130 activation could not be achieved by a single antibody, but requires the action of two distinct monoclonal antibodies [39,40].”

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• cites [40]Not matched

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The cytoplasmic part of IL-6Rα contains a tyrosine-based and a dileucine-type motif which direct sorting of IL-6Rα to the basolateral membrane of polarized cells.

“it contains a tyrosine-based and a dileucine-type motif which direct sorting of IL-6Rα to the basolateral membrane of polarized cells.”

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An independent study on the EpoR juxtamembrane intracellular region described an α-helical dependency of Epo-induced signal transduction.

“An independent study on the EpoR (erythropoietin receptor) juxtamembrane intracellular region also described an α-helical dependency of Epo-induced signal transduction [46].”

• cites [46]Not matched

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Stimulation of fibrosarcoma cells with OSM leads to pronounced phosphorylation of the IFN receptor chain 1.

“stimulation of fibrosarcoma cells with OSM leads to a pronounced phosphorylation of the IFN (interferon) receptor chain 1 [33]”

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In murine embryonic fibroblasts lacking the IFNα-IFNβ signalling complex, IL-6 signals are significantly reduced.

“in murine embryonic fibroblasts lacking the IFNα-IFNβ signalling complex IL-6 signals are significantly reduced [34].”

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The signal transducing chains gp130, LIFR and OSMR bind to JAK1, JAK2 and TYK2.

“The signal transducing chains gp130, LIFR and OSMR bind to JAK1, JAK2 and TYK2 [47][48][49][50].”

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In gp130 and the LIFR, dileucine-like motifs have been identified that are required for receptor-mediated ligand internalization.

“Indeed, in gp130 [26] and the LIFR [27] dileucine-like motifs have been identified that are required for receptor-mediated ligand internalization.”

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The naturally occurring combination of sIL-6Rα and sgp130 might act as a buffer to modulate systemic responses to circulating IL-6.

“Thus the naturally occuring combination of sIL-6Rα and sgp130 might act as a kind of buffer to modulate systemic responses to circulating IL-6 [7].”

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The C-termini of the two CBMs in the gp130 homodimer are separated by a distance of about 9 nm.

“A domain model of the IL-6 receptor complex [36], as well as the recent X-ray data [24], show that the C-termini of the two CBMs in the gp130 homodimer are separated by a distance of about 9 nm.”

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STAT1 is recruited to the more restricted consensus sequence pYXPQ (Y905LPQ and Y915MPQ in gp130).

“STAT1 is recruited to the more restricted consensus sequence pYXPQ (Y 905 LPQ and Y 915 MPQ in gp130) [84].”

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In the case of STAT3 activation after IL-6 stimulation of HepG2 cells, two distinct pathways for the serine phosphorylation have been identified: one sensitive and the other insensitive to the serine/threonine kinase inhibitor H7.

“In the case of STAT3 activation after IL-6 stimulation of HepG2 cells, two distinct pathways for the serine phosphorylation have been identified: one sensitive and the other insensitive to the serine/threonine kinase inhibitor H7 [98].”

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In prolactin-stimulated mammary epithelial cells serine phosphorylation has an impact on signal duration.

“In prolactin-stimulated mammary epithelial cells serine phosphorylation has an impact on signal duration [101].”

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Deletion of the proline-rich box1 or mutation of two critical proline residues within box1 abrogates receptor binding of JAKs to gp130, OSMR or LIFR.

“Deletion of the proline-rich box1 or mutation of two critical proline residues within box1 abrogates receptor binding of JAKs to gp130, OSMR or LIFR [49,53,54].”

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Co-expression of JAK1, JAK2 and TYK2 substantially enhances the surface expression of the human OSMR.

“Co-expression of JAK1, JAK2 and TYK2 substantially enhances the surface expression of the human OSMR.”

• cites [49]Not matched

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TYK2 prevents receptor internalization.

“Recently, it has been found that TYK2 prevents receptor internalization [69].”

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JAK2 is crucial for EpoR surface expression.

“Similarly, JAK2 is crucial for EpoR surface expression.”

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The lack of reports confirming phosphorylation of Tyr657 questions the relevance of this tyrosine phosphorylation site for STAT3 function.

“This, together with the lack of reports by other groups confirming the phosphorylation of Tyr 657 , questions the relevance of this tyrosine phosphorylation site for STAT3 function.”

For several cell lines, PKCδ associates IL-6 dependently with STAT3 and phosphorylates it on Ser727, leading to an inhibition of STAT3 DNA binding and transcriptional activity.

“For several cell lines it has been reported that PKCδ associates IL-6 dependently with STAT3 and phosphorylates it on Ser 727 , leading to an inhibition of STAT3 DNA binding and transcriptional activity [94].”

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Mutation of a single amino acid (Trp666) in the interbox1-2 region of gp130 abrogates JAK binding and thereby leads to inactivation of the receptor complex.

“Finally, also the interbox1-2 region of gp130 is critical, e.g.mutation of a single amino acid (Trp 666 ) abrogates JAK binding and thereby leads to inactivation of the receptor complex [54].”

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Phosphorylation of Tyr657 would severely impair the function of the SH2 domain, as it is located in the centre of the binding pocket responsible for specific recognition of phosphotyrosine motifs.

“Phosphorylation of this Tyr 657 would severely impair the function of the SH2 domain, as it is located in the centre of the binding pocket responsible for specific recognition of phosphotyrosine motifs.”

The Src family kinase Hck associates with an acidic region (amino acids 771-811) of gp130.

“The Src family kinase Hck has recently been shown to associate with an acidic region (amino acids 771-811) of gp130 [65].”

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The location of Tyr657 in the solved structure of STAT3β bound to DNA questions that Tyr657 is able to recruit the SH2 domain of PI3K.

“However, the location of Tyr 657 in the solved structure of STAT3β bound to DNA questions that Tyr 657 is able to recruit the SH2 domain of PI3K.”

STAT3 binds to phospho (p)YXXQ motifs (Y767RHQ, Y814FKQ, Y905LPQ and Y915MPQ in gp130; Y981QPQ, Y1001KPQ and Y1028RPQ in LIFR).

“Whereas STAT3 binds to phospho (p)YXXQ motifs (Y 767 RHQ, Y 814 FKQ, Y 905 LPQ and Y 915 MPQ in gp130; Y 981 QPQ, Y 1001 KPQ and Y 1028 RPQ in LIFR) [81,[84][85][86]”

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Signal transduction is drastically impaired if only one chain within a gp130 dimer carries the W652A mutation.

“Signal transduction is even drastically impaired if only one chain within a gp130 dimer carries the W652A mutation [55].”

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PKCδ is found in a complex with gp130 upon IL-6 stimulation.

“PKCδ (protein kinase Cδ), a kinase implicated in serine phosphorylation of STAT3 (see below), has been found in a complex with gp130 upon IL-6 stimulation.”

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Subsequent to receptor binding, the STAT factors are phosphorylated on a single tyrosine residue (Tyr701 in STAT1 and Tyr705 in STAT3).

“Subsequent to receptor binding, the STAT factors are phosphorylated on a single tyrosine residue (Tyr 701 in STAT1 and Tyr 705 in STAT3) [88,89].”

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Association of JAKs to the box1/box2 region leads to masking of a negative regulatory signal that prevents efficient surface expression of OSMR.

“association of the JAKs to the box1/box2 region leads to the masking of a negative regulatory signal, potentially a previously uncharacterized endoplasmic reticulum retention/retrieval signal, that prevents efficient surface expression.”

• cites [49]Not matched

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Although several gp130 motifs mediate STAT3 activation, they are not equivalent with respect to their potential to activate STAT factors and acute-phase protein gene promoters.

“Although several gp130 motifs mediate STAT3 activation, they are not equivalent with respect to their potential to activate STAT factors and acute-phase protein gene promoters [87].”

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The STAT1 and STAT3 phosphotyrosine motifs do not agree with the STAT3 consensus sequences deduced from the gp130 and LIFR recruitment sites.

“Interestingly, the STAT1 and STAT3 phosphotyrosine motifs (STAT1, pY 701 IKT; STAT3, pY 705 LKT) do not agree with the STAT3 consensus sequences deduced from the gp130 and LIFR recruitment sites [81,[84][85][86].”

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The partially buried side chain of Tyr657 would not be able to bind into the phosphotyrosine binding pocket of PI3K.

“In addition, the partially buried side chain of Tyr 657 would not be able to bind into the phosphotyrosine binding pocket of PI3K.”

A recent mutagenesis study has highlighted the importance of the F1 subdomain of JAK1 for the interaction with gp130.

“A recent mutagenesis study has highlighted the importance of the F1 subdomain of JAK1 for the interaction with gp130 [63].”

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Alteration of the kinase domain structure of JAK3 by staurosporine decreased the ability to bind to the common γ chain.

“it was described that alteration of the kinase domain structure of JAK3 by the kinase inhibitor staurosporine decreased the ability to bind to the common γ chain [64].”

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TYK2 is important for surface expression of the IFNα receptor 1 chain.

“TYK2 is important for surface expression of the IFNα receptor 1 chain [68].”

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Most investigators have found an increase in transcription of target genes upon cytokine-induced serine phosphorylation of STAT1, -3 and -5.

“Most investigators have found an increase in transcription of target genes upon cytokine-induced serine phosphorylation of STAT1, -3 and -5 [93,[98][99][100][101][102].”

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Dephosphorylation of STAT within the nucleus leads to export from the nucleus.

“Dephosphorylation of STAT within the nucleus leads to export from the nucleus [121].”

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Artificially dimerized STAT proteins that are not phosphorylated also accumulate in the nucleus.

“Artificially dimerized STAT proteins that are not phosphorylated also accumulate in the nucleus [110,111].”

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Tyr974 of LIFR is crucial for activation of the MAPK cascade.

“Initial analyses concerning gp130-and LIFR-mediated activation of MAPKs identified the SHP2 (SH2-domain-containing tyrosine phosphatase)-binding site Tyr 759 of gp130 [81] and Tyr 974 of LIFR to be crucial for the activation of the MAPK cascade [127].”

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The functional overlap of DNA-binding, NLS and NES sequences points to a role for DNA binding in the regulation of nucleocytoplasmic shuttling of STAT proteins.

“The functional overlap of DNA-binding, NLS and NES sequences points to a role for DNA binding in the regulation of nucleocytoplasmic shuttling of STAT proteins.”

Shc is recruited to OSMR via Tyr861 in the cytoplasmic region.

“It has been demonstrated that the adaptor protein Shc (SH2and collagen-homology-domain-containing protein) (Figure 4) is recruited to the receptor via Tyr 861 in the cytoplasmic region of the OSMR [128] (Figure 6).”

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Two other NESs were characterized in the coiled-coil region of STAT1 (residues 302-314), both containing several leucine residues that are critical for their function.

“Two other NESs were characterized in the coiled-coil region of STAT1 (residues 302-314), both containing several leucine residues that are critical for their function [109,120].”

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Tyrosine-phosphorylated SHP2 interacts with Grb2.

“Subsequently, tyrosine-phosphorylated SHP2 interacts with Grb2 [132].”

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Mutation of Tyr759 in gp130 impairs the interaction of Gab1 with SHP2 and PI3K.

“Nevertheless, mutation of Tyr 759 , the SHP2 recruitment site within gp130, impairs the interaction of Gab1 with SHP2 and PI3K, suggesting that binding of SHP2 to gp130 and its subsequent phosphorylation is a prerequisite for the interaction with Gab1.”

Continuous nucleocytoplasmic shuttling of STAT proteins occurs after stimulation and nuclear accumulation.

“Further evidence suggests that continuous nucleocytoplasmic shuttling of STAT proteins even occurs after stimulation and nuclear accumulation [126].”

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NLSs for phosphorylation-independent shuttling are different from those for phosphorylation-induced nuclear accumulation.

“NLSs for this phosphorylation-independent shuttling are different from those for phosphorylation-induced nuclear accumulation, but are not yet identified [117].”

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There seems to exist no strict requirement for the targeted movement of endocytotic vesicles for STAT nuclear translocation to occur.

“Thus there seems to exist no strict requirement for the targeted movement of endocytotic vesicles for STAT nuclear translocation to occur.”

Translocation of SHP2 to the membrane in proximity to membrane-anchored Ras is sufficient to mediate ERK activation.

“Although Gab1 integrates several signal transduction pathways, translocation of SHP2 to the membrane, in proximity to membrane anchored Ras, seems to be sufficient to mediate ERK activation, since expression of a fusion protein comprising the PH domain of Gab1 and active SHP2 induces constitutive MEK1 (MAPK/ERK kinase) and ERK2 activation [137].”

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No direct interaction of Gab1 and gp130 is required for Gab1 tyrosine phosphorylation.

“Interestingly, no direct interaction of Gab1 and gp130 is required for its tyrosine phosphorylation.”

Basic residues Lys410 and Arg413 also contribute to the NLS of dimeric STAT1.

“Adjacent to this sequence, basic residues (Lys 410 and Arg 413 ) were identified that also contribute to the NLS of dimeric STAT1 [117][118][119].”

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There is evidence that the PKCδ-mediated STAT3 Ser727 phosphorylation occurs in the nucleus.

“Moreover, there is evidence that the PKCδ-mediated STAT3 Ser 727 phosphorylation occurs in the nucleus [95].”

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Gab1 is involved in activation of the Ras-Raf-MAPK cascade.

“Another degree of complexity is added by the fact that Gab1 is also involved in the activation of the Ras-Raf-MAPK cascade.”

Mutagenesis studies on STAT5 provided the first evidence for a functional role of the DNA-binding domain in nuclear translocation.

“Nevertheless, mutagenesis studies on STAT5 provided the first evidence for a functional role of the DNA-binding domain in nuclear translocation [115].”

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OSMR does not recruit SHP2.

“In contrast with gp130 and LIFR, the OSMR does not recruit SHP2.”

OSMR is able to induce activation of the Ras-Raf-MAPK pathway.

“Nevertheless, the OSMR is also able to induce activation of the Ras-Raf-MAPK pathway.”

Unphosphorylated STATs act as transcriptional coactivators.

“The finding of unphosphorylated STAT proteins within the nucleus [122] is consistent with the well-established role of unphosphorylated STATs as transcriptional coactivators [124,125].”

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Continuous nucleocytoplasmic shuttling of STAT proteins is independent from extracellular stimulation and phosphorylation.

“Our recent investigations and work of others [117,122,123] led to the establishment of continous nucleocytoplasmic shuttling of STAT proteins that is independent from extracellular stimulation and phosphorylation.”

• cites [117]Not matched

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The SHP2-binding site Tyr759 of gp130 is crucial for activation of the MAPK cascade.

“Initial analyses concerning gp130-and LIFR-mediated activation of MAPKs identified the SHP2 (SH2-domain-containing tyrosine phosphatase)-binding site Tyr 759 of gp130 [81] and Tyr 974 of LIFR to be crucial for the activation of the MAPK cascade [127].”

• cites [81]Not matched

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Extracellular-signal-dependent translocation of STAT1 in response to IFN requires the nuclear import receptor NPI-1/importin-α5, which mediates translocation via a Ran-dependent mechanism.

“Indeed, extracellularsignal-dependent translocation of STAT1 in response to IFN requires the nuclear import receptor NPI-1/importin-α5, which mediates translocation via a Ran-dependent mechanism [107].”

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OSMR, unlike gp130 or LIFR, uses the Shc-Grb2-SOS route for activation of MAPKs.

“Thus the OSMR, unlike gp130 or the LIFR, uses the Shc-Grb2-SOS route for activation of MAPKs [128].”

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Residues located within this short sequence stretch are important for the interaction of STAT1 with the import receptor importin-α5 and therefore for nuclear import of STAT1.

“Later it turned out that residues located within this short sequence stretch are important for the interaction of STAT1 with the import receptor importin-α5 and therefore for nuclear import of STAT1 [116,117].”

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Binding of SHP2 to gp130 and its subsequent phosphorylation is a prerequisite for interaction with Gab1.

“Nevertheless, mutation of Tyr 759 , the SHP2 recruitment site within gp130, impairs the interaction of Gab1 with SHP2 and PI3K, suggesting that binding of SHP2 to gp130 and its subsequent phosphorylation is a prerequisite for the interaction with Gab1.”

IL-6-induced association of Gab1 with SHP2 leads to activation of ERK2.

“Finally, IL-6-induced association of Gab1 with SHP2 leads to activation of ERK2 [135].”

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Unphosphorylated STAT proteins are present within the nucleus.

“The finding of unphosphorylated STAT proteins within the nucleus [122] is consistent with the well-established role of unphosphorylated STATs as transcriptional coactivators [124,125].”

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Both IRS-1 and Gab1 may couple gp130 to PI3K activation.

“Similarly, PI3K associates with the IRS-1 (insulin receptor substrate-1) adaptor in response to OSM [150], suggesting that both IRS-1 and Gab1 may couple gp130 to PI3K activation.”

Binding of SH2 domains to phosphotyrosine motifs of receptors or adapters unfolds SHP2, leading to enzymic activity.

“Binding of the SH2 domains to phosphotyrosine motifs of receptors or adapters unfolds the protein, leading to enzymic activity [153][154][155].”

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• cites [154]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [155]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

PIAS3 is specific for inhibition of STAT3-mediated gene expression after IL-6 stimulation.

“Whereas PIAS1 specifically inhibits DNA binding of activated STAT1 and thus STAT1-mediated gene induction (after IFN stimulation) [179], PIAS3 was found to be specific for the inhibition of STAT3-mediated gene expression (after IL-6 stimulation) [178].”

• cites [178]Not matched

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PIAS1 specifically inhibits DNA binding of activated STAT1 and thus STAT1-mediated gene induction after IFN stimulation.

“Whereas PIAS1 specifically inhibits DNA binding of activated STAT1 and thus STAT1-mediated gene induction (after IFN stimulation) [179], PIAS3 was found to be specific for the inhibition of STAT3-mediated gene expression (after IL-6 stimulation) [178].”

• cites [179]Not matched

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The nuclear phosphatase that counteracts IFNγ-activated STAT1 is the nuclear isoform of T-cell PTP TC45.

“Meanwhile, this phosphatase has been identified as the nuclear isoform of the T-cell PTP TC45 [174,175].”

• cites [174]Not matched

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• cites [175]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

PI3K associates with the IRS-1 adaptor in response to OSM.

“Similarly, PI3K associates with the IRS-1 (insulin receptor substrate-1) adaptor in response to OSM [150], suggesting that both IRS-1 and Gab1 may couple gp130 to PI3K activation.”

• cites [150]Not matched

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Interaction of PIAS proteins with STAT factors seems to require tyrosine phosphorylation of the STAT proteins.

“The interaction of PIAS proteins with STAT factors seems to require tyrosine phosphorylation of the STAT proteins.”

STAT3 is a direct substrate of SHP2, evidenced by detection of STAT3-SHP2 complexes.

“Further evidence for STAT3 as a direct substrate of SHP2 comes from the detection of STAT3-SHP2 complexes [163].”

• cites [163]Not matched

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PIAS1 may prevent dephosphorylation by masking the T-cell PTP binding region of nonmethylated STAT1.

“Since both T-cell PTP and PIAS1 associate with the N-terminus of STAT1 (see below), PIAS1 may prevent dephosphorylation by preferentially masking the T-cell PTP binding region of nonmethylated STAT1 [176].”

• cites [176]Not matched

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In human Hep3B hepatoma cells, IL-6 leads to activation of the PI3K/Akt pathway necessary for the anti-apoptotic effect of IL-6 during TGFβ treatment.

“Moreover, in human Hep3B hepatoma cells IL-6 leads to activation of the PI3K/Akt pathway necessary for the anti-apoptotic effect of IL-6 during transforming growth factor β treatment [148].”

• cites [148]Not matched

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After IL-6 stimulation, Gab1 interacts with PI3K.

“After IL-6 stimulation the adaptor protein Gab1 (see the subsection above entitled 'Activation of MAPK cascades: one tyrosine to make things more complicated') interacts with PI3K [135].”

• cites [135]Not matched

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In cardiac myocytes, gp130 conveys signals through the PI3K pathway leading to prevention of doxorubicin-induced apoptosis.

“In cardiac myocytes gp130 conveys signals through this pathway which lead to prevention of doxorubicin-induced apoptosis [143].”

• cites [143]Not matched

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Substitution of Tyr759 of gp130 with phenylalanine impairs SHP2 recruitment and phosphorylation.

“Tyr 759 of gp130 appears to have multivalent functions for signalling; substitution with phenylalanine impairs SHP2 recruitment and phosphorylation [81] and leads to enhanced 157,158], as well as LIF and OSM, signal transduction [159].”

• cites [81]Not matched

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Overexpression of dominant-negative SHP2 mutants leads to enhanced receptor, JAK, STAT and SHP2 phosphorylation.

“Overexpression of dominant-negative SHP2 mutants leads to enhanced receptor, JAK, STAT and SHP2 phosphorylation [160].”

• cites [160]Not matched

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The crystal structure of SHP2 suggests that, in the absence of a tyrosine-phosphorylated binding partner, the N-terminal SH2 domain covers the active site and inhibits enzymic activity.

“The crystal structure of SHP2 suggests that, in the absence of a tyrosinephosphorylated binding partner, the N-terminal SH2 domain covers the active site and thereby inhibits the enzymic activity [152].”

• cites [152]Not matched

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IL-6-type cytokines can lead to activation of the PI3K cascade.

“IL-6-type cytokines can lead to the activation of yet an additional signalling cascade involving PI3K.”

PIASy does not affect STAT1 DNA-binding activity.

“In contrast with PIAS1, however, it did not affect STAT1 DNAbinding activity.”

PTP SHP2 is recruited to cytoplasmic Tyr759 of activated gp130.

“First evidence for the contribution of a phosphatase in IL-6 signalling was obtained by the finding that the PTP SHP2 is recruited to the cytoplasmic Tyr 759 of activated gp130 [81,151].”

• cites [81]Not matched

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• cites [151]Not matched

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SHP2 dephosphorylates STAT1 pTyr701 and pSer727 as a dual-specificity phosphatase.

“In the case of STAT1, SHP2 has been described as a dual-specificity phosphatase that dephosphorylates pTyr 701 and pSer 727 [164].”

• cites [164]Not matched

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PIASy inhibits STAT1-mediated gene activation.

“Recently, PIASy was found to also inhibit STAT1-mediated gene activation [181].”

• cites [181]Not matched

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PIAS1 preferentially associates with unmethylated STAT1.

“As mentioned above, PIAS1 preferentially associates with unmethylated STAT1 [106].”

• cites [106]Not matched

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SHP2 plays a negative regulatory role as a tyrosine phosphatase in the Jak/STAT pathway.

“However, SHP2 also plays a negative regulatory role as a tyrosine phosphatase in the Jak/STAT pathway [160] (as indicated in Figure 8).”

• cites [160]Not matched

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PIAS proteins are important transcriptional co-regulators of the JAK/STAT pathway.

“Initially identified as Gu/RNA helicase II-binding protein (PIAS1) [177], it rapidly became clear that PIAS proteins are important transcriptional co-regulators of the JAK/STAT pathway [178,179].”

• cites [178]Not matched

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• cites [179]Not matched

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Phosphorylated Tyr542 and Tyr580 interact with the N- and C-terminal SH2 domains, relieving the PTP domain from N-terminal SH2-domain-mediated inhibition.

“Subsequently, these phosphotyrosines interact with the N-and C-terminal SH2-domains respectively, relieving the PTP domain from the N-terminal SH2-domain-mediated inhibition [156] (Figure 7).”

• cites [156]Not matched

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STAT1 methylated at Arg31 is a better substrate for T-cell PTP than non-methylated STAT1.

“Interestingly, STAT1 methylated at Arg 31 is a better substrate for T-cell PTP than non-methylated STAT1.”

SHP2 becomes activated by phosphorylation of tyrosine residues 542 or 580 within its C-terminal part.

“SHP2 also becomes activated by the phosphorylation of tyrosine residues 542 or 580 within the C-terminal part of the enzyme.”

In MK2-deficient macrophages, the half-life of IL-6 mRNA is reduced by more than 10-fold.

“It was shown in MK2-deficient macrophages that the half-life of IL-6 mRNA was reduced by more than 10-fold.”

The KIR region of SOCS1 is thought to bind the substrate binding site of the kinase domain and thereby inhibit its catalytic activity.

“The KIR region is thought to bind to the substrate binding site of the kinase domain and thereby to inhibit its catalytic activity [195].”

• cites [195]Not matched

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SOCS1 targets JAK2, Tel-JAK2 and IRS1/2, as well as Vav, to degradation.

“Consistent with the postulated E3-ligase function are new findings that SOCS1 targets JAK2, Tel-JAK2 and IRS1/2, as well as Vav, to degradation [208][209][210][211][212].”

• cites [208]Not matched

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• cites [209]Not matched

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• cites [210]Not matched

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SOCS1 and SOCS3 act on JAKs and thereby inhibit phosphorylation of gp130, STATs and the JAKs themselves.

“Both have been shown to act on the JAKs, and thereby inhibit the phosphorylation of gp130, STATs and the JAKs themselves [190,192].”

• cites [190]Not matched

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• cites [192]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

SOCS3 is tyrosine phosphorylated in response to IL-2, Epo, EGF and PDGF.

“In the case of SOCS3, tyrosine phosphorylation in response to IL-2, Epo, EGF and PDGF was reported [139,216].”

• cites [139]Not matched

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• cites [216]Not matched

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PIASy appears to act as a transcriptional co-repressor of STAT1.

“PIASy rather appears to act as a transcriptional co-repressor of STAT1.”

SOCS3 associates with specific phosphotyrosine motifs within activated cytokine receptors, such as gp130, EpoR, leptin receptor and the granulocyte colony-stimulating factor receptor.

“In contrast with SOCS1, despite the fact that it can also bind to JAKs and that it contains a KIR region [196], SOCS3 associates with specific phosphotyrosine motifs within activated cytokine receptors, such as gp130, EpoR, leptin receptor and the granulocyte colony-stimulating factor receptor [197][198][199][200][201][202][203].”

• cites [197]Not matched

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• cites [198]Not matched

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• cites [199]Not matched

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LPS inhibits IFNγ-dependent STAT1 activation via induction of SOCS3.

“A similar mechanism has been discovered for IFNγ signalling, where LPS inhibits IFNγ -dependent STAT1 activation also via the induction of SOCS3 [230].”

• cites [230]Not matched

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The affinity of SOCS3 to bind gp130 peptides is slightly higher than that of SHP2.

“In fact, the affinity of SOCS3 to bind to gp130 peptides is even slightly higher than that of SHP2 [204].”

• cites [204]Not matched

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Janus kinases JAK1, JAK2, TYK2 and gp130 show intermediate half-lives.

“The Janus kinases JAK1, JAK2, TYK2 and gp130 show intermediate half-lives.”

Inhibition of IL-6-mediated STAT3 activation by LPS/TNFα is most likely due to induction of de novo synthesis of the JAK-inhibitor SOCS3.

“This inhibition is most likely due to induction of the de novo synthesis of the JAK-inhibitor SOCS3 [229].”

• cites [229]Not matched

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The half-life of STAT3β is reduced by almost 50% compared with the half-life of STAT3α.

“Interestingly, the half-life of STAT3β, a splice variant of STAT3α, is reduced by almost 50 % compared with the half-life of STAT3α.”

Sumoylation may target transcription factors to nuclear bodies where they bind other sumoylated proteins and become transcriptionally active or inactive.

“Sumoylation may play a critical role in targeting transcription factors to nuclear bodies, where they bind to other sumoylated proteins, such as PML (promyelocytic leukaemia) or the co-repressor Sp100, and thereby become transcriptionally active or inactive [186,187].”

• cites [186]Not matched

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• cites [187]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Stress-activated p38 MAPK stabilizes the mRNA of many cytokines, including IL-6, by activation of MK2.

“The stress-activated p38 MAPK has been shown to play an important role in stabilizing the mRNA of many cytokines, including IL-6, by activation of MK2 (MAPKAPK2, MAPK-activated protein kinase 2) [217].”

• cites [217]Not matched

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SOCS3 binds pTyr759 of gp130 with much higher affinity than pTyr1007 within the activation loop of JAK2.

“Binding studies with phosphopeptides suggest that SOCS3 binds pTyr 759 of gp130 with much higher affinity than pTyr 1007 within the activation loop of JAK2 [198].”

• cites [198]Not matched

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LPS and TNFα inhibit IL-6-mediated STAT3 activation in macrophages.

“For example, LPS (lipopolysaccharide) and the pro-inflammatory cytokine TNFα have been shown to inhibit IL-6-mediated STAT3 activation in macrophages.”

The half-lives of various players involved in IL-6 signalling differ substantially.

“It has been reported that the half-lives of the various players involved in IL-6 signalling differ substantially (Table 1) [222,223].”

• cites [222]Not matched

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• cites [223]Not matched

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Both SOCS3-dependent and SOCS3-independent inhibitory mechanisms of pro-inflammatory stimuli depend on the p38 stress kinase.

“Interestingly, both SOCS3-dependent and SOCS3-independent inhibitory mechanisms of pro-inflammatory stimuli depend on the p38 stress kinase [229,231,233].”

• cites [229]Not matched

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• cites [231]Not matched

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• cites [233]Not matched

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Mutations within the box region of SOCS1, as well as serine phosphorylation, which disrupt elongin C binding, stabilize SOCS1.

“Mutations within the box region of SOCS1, as well as serine phosphorylation, which disrupt elongin C binding, have been shown to stabilize SOCS1 [213,214].”

• cites [213]Not matched

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• cites [214]Not matched

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At least some PIAS family members display their activity in the nucleus, located in specific nuclear bodies attached to the nuclear scaffold.

“While earlier studies suggested that PIAS proteins might act in the cytoplasm, the picture that emerges from recently published work is that at least some members of this family display their activity in the nucleus.Here, they are located in specific nuclear bodies [182,183] attached to the nuclear scaffold [184].”

• cites [182]Not matched

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• cites [183]Not matched

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• cites [184]Not matched

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SOCS proteins may be part of E3-ubiquitin ligases in complex with elongins B and C, Rbx1 and Cul5.

“Recent work suggests that SOCS proteins may be part of E3-ubiquitin ligases in complex with elongins B and C, as well as Rbx1 (RING box protein 1) and Cul5 (cullin 5) [206,207].”

• cites [206]Not matched

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• cites [207]Not matched

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PIAS proteins exhibit E3-SUMO-ligase activity.

“With respect to this finding, it is of interest that PIAS proteins exhibit E3-SUMO (small ubiquitin-related modifier)-ligase activity [185,186].”

• cites [185]Not matched

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• cites [186]Not matched

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There are two largely distinct modes of negative regulation of gp130 activity: feedback inhibition by SOCS3 and/or dephosphorylation of phosphorylated JAKs, receptors and STATs.

“Although both SOCS3 and SHP2 are recruited to the same site within the native gp130, it is suggested that there are two largely distinct modes of negative regulation of gp130 activity: through the feedback inhibition by SOCS3 and/or the dephosphorylation of phosphorylated JAKs, receptors and STATs [160].”

• cites [160]Not matched

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CIS competes with STAT5 for recruitment sites within EpoR and thereby modulates the JAK2/STAT5 pathway.

“CIS, which was the first member to be identified, was shown to compete with STAT5 for recruitment sites within the EpoR and to thereby modulate the JAK2/STAT5 pathway [189,194].”

• cites [189]Not matched

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• cites [194]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

IL-1, TNF-α and LPS inhibit IL-6-dependent STAT activation in macrophages through mechanisms that do not depend on de novo protein synthesis.

“Additional mechanisms for inhibiting IL-6 signalling by pro-inflammatory cytokines may exist, since other data show that IL-1, TNF-α and LPS inhibit IL-6-dependent STAT activation in macrophages through mechanisms which do not depend on de novo protein synthesis [231,232].”

• cites [231]Not matched

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• cites [232]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

SOCS1 inhibits signal transduction by binding to the activation loop of JAKs via its SH2 domain.

“SOCS1 inhibits signal transduction by binding to the activation loop of the JAKs via its SH2 domain.”

SOCS1 blocks JAK activity more efficiently than SOCS3.

“This difference in the inhibitory mechanisms of SOCS1 and SOCS3 is also reflected in the fact that SOCS1 blocks JAK activity more efficiently than SOCS3 [205].”

• cites [205]Not matched

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EZI may augment STAT3 activity by keeping it in the nucleus.

“Thus, EZI may augment STAT3 activity by keeping it in the nucleus.”

STAT5B limits NF-κB-mediated signalling by competing for CBP.

“By a similar mechanism STAT5B limits NF-κB-mediated signalling [254].”

• cites [254]Not matched

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Tandem organization of STAT-binding sites is essential for binding of tetrameric STAT3 to the α2M promoter.

“This tandem organization of STAT-binding sites has also been emphasized to be essential for binding of tetrameric STAT3 to the α 2 M promoter [245].”

• cites [245]Not matched

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A balanced ratio of NF-κB and STAT3 is essential for activating the α2M promoter.

“Interestingly, although NF-κB acts as a competitive inhibitor for STAT3 DNA-binding, at least one intact NF-κB and one intact STAT3 consensus site is crucial for the STAT3-dependent activation of the α 2 M gene promoter [236], suggesting that a balanced ratio of NF-κB and STAT3 is essential for activating the α 2 M promoter.”

ERK1/2 MAPK play a crucial role in the inhibitory effect of ionomycin or PMA on IL-6-mediated STAT activation.

“Instead ERK1/2 MAPK were found to play a crucial role [234].”

• cites [234]Not matched

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STAT-binding sites are often in close proximity to binding sites for other transcription factors, such as NF-IL6, NF-κB, AP-1 and glucocorticoid receptor.

“STAT-binding sites are often in close proximity to binding sites for other transcription factors, such as nuclear factor-IL6 [237], NF-κB [238], activator protein-1 [224,[239][240][241] and glucocorticoid receptor [242], making a co-operative action of these factors with STATs in gene regulation most likely.”

• cites [237]Not matched

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• cites [238]Not matched

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• cites [224]Not matched

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STAT3 and EZI physically interact as demonstrated by co-immunoprecipitation.

“STAT3 and EZI physically interact as demonstrated by co-immunoprecipitation.”

The C-terminal transactivation domains of STAT1, STAT3 and STAT5 interact with CBP/p300.

“The C-terminal transactivation domains of STAT1, STAT3 and STAT5 are known to interact with CBP/p300 [239,[250][251][252].”

• cites [239]Not matched

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• cites [250]Not matched

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• cites [251]Not matched

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FKHR is inactivated by Akt/protein kinase B-mediated serine/threonine phosphorylation.

“FKHR is inactivated by Akt/protein kinase B-mediated serine/threonine phosphorylation.”

Binding of the N- or C-terminal SH2 domain of SHP2 by specific phosphotyrosine-containing motifs releases the block on its PTPase activity.

“Binding of the N-or C-terminal SH2 domain by specific phosphotyrosine-containing motifs releases the block.”

• cites [156]Not matched

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In the promoters of the rat α2M and human α1-antichymotrypsin genes, STAT3-binding sites are arranged as a tandem.

“Moreover, in the promoters of the rat α 2 M and the human α 1antichymotrypsin genes, STAT3-binding sites are arranged as a tandem [243,244], suggesting that formation of multimers on clustered binding sites also represents a regulatory step in STATdependent gene activation.”

• cites [243]Not matched

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• cites [244]Not matched

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IL-1β inhibits IL-6-induced acute-phase protein synthesis in hepatocytes.

“IL-1β is also known to inhibit IL-6-induced acute-phase protein synthesis in hepatocytes [235].”

• cites [235]Not matched

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In the inactive state, the N-terminal SH2 domain of SHP2 sterically hinders access of phosphotyrosine substrates to the PTP domain and thus blocks PTPase activity.

“In the inactive state, the N-terminal SH2 domain of SHP2 sterically hinders access of phosphotyrosine substrates to the PTP domain and thus blocks PTPase activity.”

• cites [156]Not matched

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At least one intact NF-κB and one intact STAT3 consensus site is crucial for STAT3-dependent activation of the α2M gene promoter.

“Interestingly, although NF-κB acts as a competitive inhibitor for STAT3 DNA-binding, at least one intact NF-κB and one intact STAT3 consensus site is crucial for the STAT3-dependent activation of the α 2 M gene promoter [236], suggesting that a balanced ratio of NF-κB and STAT3 is essential for activating the α 2 M promoter.”

• cites [236]Not matched

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NF-κB acts as a competitive inhibitor for STAT3 DNA-binding.

“The first evidence for a competition of STAT3 and NF-κB for the α 2 M promoter binding was provided by Zhang and Fuller [246] on an isolated binding site within the α 2 M promoter.”

• cites [246]Not matched

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FKHR can modulate IL-6-induced transcriptional activity by enhancing STAT3 action.

“These results indicate that FKHR can modulate the IL-6-induced transcriptional activity by enhancing STAT3 action.”

NF-κB has a dual, negative as well as positive, regulatory function in acute-phase protein gene induction.

“This indicates a dual, negative as well as positive, regulatory function of NF-κB in acute-phase protein gene induction.”

STAT1 abolishes AP-1/ets transcriptional activity by competing for CBP binding.

“Such a regulatory function has been shown for STAT1 which abolishes activator protein-1/ets transcriptional activity by competing for CBP binding [239].”

• cites [239]Not matched

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NF-κB mediates IL-1β-dependent suppression of IL-6-induced α2M expression in liver cells.

“Instead, NF-κB was identified as a mediator for IL-1β-dependent suppression of IL-6-induced α 2 M (α 2 -macroglobulin) expression in liver cells [236].”

• cites [236]Not matched

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