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IL6 — JAK2
Pathways - manually collected, often from reviews:
-
BioCarta role of erbb2 in signal transduction and oncology:
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130/JAKs complex (IL6-IL6R-LRPPRC-JAK2_JAK1_JAK3)
→
STAT3
(modification, activates)
-
BioCarta il 6 signaling pathway:
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130/JAKS complex (JAK2_JAK1_JAK3-LRPPRC-IL6R-IL6)
→
STAT3
(modification, activates)
-
BioCarta il 6 signaling pathway:
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130/JAKS complex (JAK2_JAK1_JAK3-LRPPRC-IL6R-IL6)
→
JAKs (JAK2/JAK1/JAK3)
(modification, collaborate)
-
BioCarta il 6 signaling pathway:
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130/JAKS complex (JAK2_JAK1_JAK3-LRPPRC-IL6R-IL6)
→
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130 complex (IL6-IL6R-LRPPRC)
(modification, collaborate)
-
BioCarta il 6 signaling pathway:
JAKs (JAK2/JAK1/JAK3)
→
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130 complex (IL6-IL6R-LRPPRC)
(modification, collaborate)
-
BioCarta role of erbb2 in signal transduction and oncology:
JAKs (JAK2/JAK1/JAK3)
→
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130 complex (IL6-IL6R-LRPPRC)
(modification, collaborate)
-
BioCarta role of erbb2 in signal transduction and oncology:
JAKs (JAK2/JAK1/JAK3)
→
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130/JAKs complex (IL6-IL6R-LRPPRC-JAK2_JAK1_JAK3)
(modification, collaborate)
-
BioCarta role of erbb2 in signal transduction and oncology:
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130 complex (IL6-IL6R-LRPPRC)
→
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130/JAKs complex (IL6-IL6R-LRPPRC-JAK2_JAK1_JAK3)
(modification, collaborate)
-
BioCarta il 6 signaling pathway:
IL-6/IL-6/IL-6R-alpha/IL-6R-alpha/GP130/GP130/JAKS complex (JAK2_JAK1_JAK3-LRPPRC-IL6R-IL6)
→
SHC/GRB2/SOS-1 complex (SOS1-GRB2-SHC1)
(modification, activates)
-
NCI Pathway Database IL6-mediated signaling events:
IL6/IL6RA/gp130 (dimer)/JAK2/JAK2/LMO4 complex (IL6-IL6R-IL6ST-JAK2-LMO4)
→
IL6/IL6RA complex (IL6-IL6R)
(modification, collaborate)
Boulanger et al., Science 2003, Novotny-Diermayr et al., J Biol Chem 2005, Hibi et al., Cell 1990, Taga et al., Cell 1989, Narazaki et al., Proc Natl Acad Sci U S A 1994, Lütticken et al., Science 1994, Stahl et al., Science 1994
Evidence: mutant phenotype, assay, physical interaction, other species
-
NCI Pathway Database IL6-mediated signaling events:
IL6/IL6RA/gp130 (dimer)/JAK2/JAK2/LMO4 complex (IL6-IL6R-IL6ST-JAK2-LMO4)
→
gp130 (dimer)/JAK2/JAK2/LMO4 complex (JAK2-IL6ST-LMO4)
(modification, collaborate)
Boulanger et al., Science 2003, Novotny-Diermayr et al., J Biol Chem 2005, Hibi et al., Cell 1990, Taga et al., Cell 1989, Narazaki et al., Proc Natl Acad Sci U S A 1994, Lütticken et al., Science 1994, Stahl et al., Science 1994
Evidence: mutant phenotype, assay, physical interaction, other species
-
NCI Pathway Database IL6-mediated signaling events:
IL6/IL6RA complex (IL6-IL6R)
→
gp130 (dimer)/JAK2/JAK2/LMO4 complex (JAK2-IL6ST-LMO4)
(modification, collaborate)
Boulanger et al., Science 2003, Novotny-Diermayr et al., J Biol Chem 2005, Hibi et al., Cell 1990, Taga et al., Cell 1989, Narazaki et al., Proc Natl Acad Sci U S A 1994, Lütticken et al., Science 1994, Stahl et al., Science 1994
Evidence: mutant phenotype, assay, physical interaction, other species
-
Reactome Reaction:
IL6
→
JAK2
(reaction)
Hibi et al., Cell 1990, Taga et al., Cell 1989, Hemmann et al., J Biol Chem 1996, Schaper et al., Biochem J 1998
-
Reactome Reaction:
IL6
→
JAK2
(indirect_complex)
Hibi et al., Cell 1990, Taga et al., Cell 1989
Text-mined interactions from Literome
Wang et al., Oncogene 2000
:
PD180970 did not affect MAPK activation by PDGF or the
JAK dependent
activation of Stat3 by
interleukin-6
Iwamoto et al., Oncogene 2000
(Acute-Phase Reaction) :
Furthermore, in vitro kinase assay indicated that JAB suppressed hyperactivation of
JAK1/JAK2 and JAK1
induced by IFNgamma and
IL-6 plus sIL-6R respectively, but not v-Src induced basal JAK1/JAK2 activity
Schieffer et al., Circ Res 2000
:
Inhibition of
JAK2 by its inhibitor AG490 ( 10 micromol/L )
blocked not only JAK2 activation but also
IL-6 synthesis
Song et al., Zhonghua Xue Ye Xue Za Zhi 2000
(Multiple Myeloma) :
The biological function of
IL-6 on Sko-007 cells is
mediated by the activation of
Jak/STAT and Ras/NF-IL-6 signal transduction pathways
Kuo et al., Oncogene 2001
:
In Hep3B cells, the
JAK/STAT3 , ERK, and PI 3-K/Akt pathways were
activated by
IL-6 stimulation
Song et al., Zhonghua Zhong Liu Za Zhi 2001
(Multiple Myeloma) :
( 1 ) IL-6 could promote the proliferation of U266 cells, ( 2 ) both
JAK/STAT and Ras/NF-IL-6 signal transduction pathways were
activated by
IL-6 in the U266 cells and ( 3 ) Cell proliferation and activation of the two IL-6 signal transduction pathways were inhibited by Forskolin ; down regulating the actiration of these two signal transduction pathways at the same time
Legendre et al., J Biol Chem 2003
:
JAK/STAT but not ERK1/ERK2 pathway
mediates interleukin (IL)-6/soluble
IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes ... In the present study, we show for the first time that
interleukin-6 (IL) , in the presence of its soluble receptor ( sIL-6R ),
induces activation of JAK1,
JAK2 , and STAT1/STAT3 proteins in bovine articular chondrocytes
Okugawa et al., Am J Physiol Cell Physiol 2003
(Gram-Negative Bacterial Infections) :
Finally, we show that
JAK2 is
involved in the production of IL-1beta and
IL-6
Fasshauer et al., Biochem Biophys Res Commun 2004
:
Studies using pharmacological inhibitors suggested that the positive effects of GH and
IL-6 on MCP-1 synthesis are at least in part
mediated by
janus kinase 2 and p44/42 mitogen activated protein kinase
Fasshauer et al., J Endocrinol 2004
(Insulin Resistance) :
Furthermore, stimulation experiments and studies using pharmacologic inhibitors suggested that the positive effect of TNFalpha, GH and
IL-6 on SOCS-1 mRNA is, at least in part,
mediated by
Janus kinase (Jak) 2
Watanabe et al., Am J Nephrol 2004
(Arteriosclerosis) :
Rat VSMC were stimulated with
IL-6 in the
presence or absence of a
JAK 2 inhibitor, and the activation of STAT 3 ( by Western ), MCP-1 ( by ELISA ) and DNA synthesis ( by ( 3 ) H-thymidine incorporation ) was determined
Siavash et al., Br J Cancer 2004
(Carcinoma, Squamous Cell...) :
Abrogation of
IL-6 mediated
JAK signalling by the cyclopentenone prostaglandin 15d-PGJ ( 2 ) in oral squamous carcinoma cells ... Importantly, 15d-PGJ ( 2 ) selectively abrogated constitutive and
IL-6 mediated
JAK phosphorylation without affecting EGFR activated levels ... Our findings provide the first evidence for 15d-PGJ ( 2 ) -mediated downregulation of constitutive and
IL-6 induced
JAK signalling in cancer and support that JAK inhibition and suppression of EGFR independent Stat3 activation by 15d-PGJ ( 2 ) represent a promising approach for induction of apoptosis in oral SCC cells
To et al., Br J Cancer 2004
(Cell Transformation, Neoplastic...) :
The
interleukin mediated
Janus kinase ( JAK ) /STAT pathway plays a crucial role in carcinogenesis
Dawn et al., Cardiovasc Res 2004
(Myocardial Infarction...) :
Myocardial
IL-6 protein expression,
activation of Janus kinase (JAK) 1 and
JAK2 , and signal transducers and activators of transcription ( STAT ) 1 and STAT3 after ischemic PC protocol were examined
Fasshauer et al., J Endocrinol 2004
(Acute-Phase Reaction) :
Inhibitor studies suggested that the positive effect of
IL-6 on SAA3 expression is at least in part
mediated by
Janus kinase 2
Kimura et al., Proc Natl Acad Sci U S A 2005
:
Suppressor of cytokine signaling-1 selectively
inhibits LPS induced
IL-6 production by regulating
JAK-STAT
Karadag et al., Blood 2006
(MAP Kinase Signaling System...) :
Furthermore, inhibitors of p38 MAPK and cPLA2, but not NF-kappaB and
JAK2 , signaling pathways
inhibited ADAM-9 induced
IL-6 production by hOBs ( P < .01 )
Shouda et al., Cancer Lett 2006
(Histiocytoma, Malignant Fibrous) :
The
JAK2 kinase inhibitor, tyrphostin AG490, suppressed the growth of MFH cells and
inhibited the secretion of
IL-6
Lee et al., Mol Cancer Ther 2006
(Carcinoma, Squamous Cell...) :
We conclude that SOCS-1 methylation status can differentially affect STAT3
activation by
IL-6R and EGFR through
JAK or MEK in different HNSCC and response to pharmacologic antagonists
O'Hara et al., Biochem J 2007
:
Inhibition with siRNA ( small interfering RNA ) targeting the SFK Lck, but not dominant negative
JAK ( Janus kinase ),
prevented Cr ( VI ) -stimulated phosphorylation of both STAT3 isoforms and induction of
IL-6
Muto et al., Mol Cancer Ther 2007
(Multiple Myeloma) :
Emodin inhibited
interleukin-6 induced activation of
Janus activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 ( STAT3 ), followed by the decreased expression of Mcl-1
Yu et al., Int J Biochem Cell Biol 2008
:
SOCS 3 and PPAR-gamma ligands
inhibit the expression of
IL-6 and TGF-beta1 by regulating
JAK2/STAT3 signaling in pancreas
Suh et al., J Cell Physiol 2009
:
IL-6 increased
Janus Kinase (JAK)-2 , signal transducer and activator of transcription ( STAT ) -3 phosphorylation, intracellular Ca ( 2+ ) concentration, and PKC phosphorylation
Gong et al., Mol Nutr Food Res 2009
(Prostatic Neoplasms) :
Moreover, an antioxidant reagent, N-acetyl-L-cysteine (NAC) which suppresses reactive oxygen species ( ROS ) generation, reversed the early inhibitory effects of PEITC on cell proliferation, constitutive or
IL-6 mediated
JAK-STAT3 phosphorylation in PCa cells
Radtke et al., J Cell Sci 2010
:
We show that p38, activated by IL-1beta, TNFalpha or environmental stress, impairs
IL-6 induced
JAK/STAT signalling through phosphorylation of the common cytokine receptor subunit gp130 and its subsequent internalisation and degradation
Tanabe et al., Journal of neuroinflammation 2010
(Glioma) :
The
Janus family of tyrosine kinase ( JAK ) inhibitor I, an inhibitor of JAK 1, 2 and 3, attenuated TNF-alpha induced phosphorylation of STAT3 and significantly
reduced TNF-alpha stimulated
IL-6 release
Nakaya et al., Leuk Res 2011
(Multiple Myeloma) :
Further, AF inhibited constitutive and
IL-6 induced activation of
JAK2 and phosphorylation of STAT3 followed by the decreased expression of Mcl-1
Tseng et al., Cytokine 2010
:
We conclude that primary human thymic epithelial cells produce GRO-alpha and that its expression is regulated primarily by autocrine IL-6 and
IL-6 activated
Jak2 signaling
Liu et al., Neurotox Res 2011
:
These results suggest that
IL-6 protects neurons against NMDA induced apoptosis, and that the IL-6 neuroprotection is jointly
mediated by
JAK-STAT3 and PI3K-Akt signaling pathways
Huang et al., Molecular cancer 2010
(Adenocarcinoma...) :
Our biochemical and genetic studies clearly demonstrated that
Jak2/Stat3 , in combination with other IL-6 downstream pathways,
contributed frequently and substantially to
IL-6 autocrine production in a broad spectrum of cancer cell lines as well as in clinical cancer samples
Ngo et al., Nature 2011
(Burkitt Lymphoma...) :
The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-?B signalling,
JAK kinase
activation of STAT3, and secretion of
IL-6 , IL-10 and interferon-ß
Tanabe et al., Journal of neuroinflammation 2011
:
The IL-1ß stimulated levels of
IL-6 were
suppressed by wedelolactone ( an inhibitor of I?B kinase ), SP600125 ( an inhibitor of SAPK/JNK ), and
JAK inhibitor I ( an inhibitor of JAK 1, 2 and 3 )
Migita et al., J Rheumatol 2011
(Acute-Phase Reaction...) :
Our data indicated that CP690,550 blocked
IL-6 induced
JAK2/STAT3 activation , as well as the induction of A-SAA
Betts et al., Blood 2011
:
JAK2 inhibition also
reduces the production of
IL-6 and TNF-a in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells
Gu et al., Molecular cancer 2011
(Carcinoma, Hepatocellular...) :
Then,
IL-6 in turn
activated JAK2/STAT3 signaling and subsequently up-regulated its downstream targets IL-8, MMP2, and VEGF
Ge et al., Prostate 2012
(Prostatic Neoplasms) :
IL-6 activated
JAK2 and STAT3 pathways in LNCaP-C3 cells but not in LNCaP-S17 cells
Yang et al., Cancer Biol Ther 2012
(Neuroblastoma) :
Sorafenib inhibits endogenous and
IL-6/S1P induced
JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis
Dittrich et al., Molecular bioSystems 2012
:
Misregulated
interleukin-6 (IL-6) induced
Jak/STAT signaling contributes to many diseases
Nam et al., J Pept Sci 2012
:
Inhibition of
JAK ( STAT1/STAT5 kinase ) with AG490 markedly
reduced the production of
IL-6 and TNF-a in macrophages
Tian et al., PloS one 2012
(Melanoma) :
Accordingly, SOID-8 inhibited
IL-6 induced
activation of STAT3 and
JAK2 in melanoma cells
Soth et al., J Med Chem 2013
:
Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1 dependent IL-2 stimulated pathway over a
JAK1/JAK2/Tyk2 dependent
IL-6 stimulated pathway
Russell et al., Islets 2013
:
Differential
effects of interleukin-13 and
interleukin-6 on
Jak/STAT signaling and cell viability in pancreatic ß-cells
Andrés et al., Exp Dermatol 2013
(MAP Kinase Signaling System...) :
Tyr705 phosphorylation was induced by
IL-6 and IL-20 in a
Jak2 dependent manner, and moreover, phosphorylation of Tyr705 produced a strong increase in STAT3 transcriptional activity
Muraoka et al., Clin Exp Rheumatol 2013
(Arthritis, Rheumatoid) :
Effects of inhibitors of
janus kinase 2 (JAK2) , phosphatidylinositol 3-kinase (PI3K), and mitogen activated protein kinase ( MAPK ) on
IL-6 production were evaluated
Fang et al., PloS one 2013
:
Further investigation of the underlying mechanism revealed simvastatin could exert the anti-tumor effects by suppressing
IL-6 induced phosphorylation of
JAK2 and STAT3
Lai et al., PloS one 2013
:
Additionally,
IL-6 mediated angiotensinogen expression through the Janus kinase ( JAK ) /signal transducer and activator of transcription 3 ( STAT3 ) and
JAK/p38 signaling ...
IL-6 mediated signaling,
JAK2 , STAT3 and p38 inhibitors reduced angiotensinogen expression in the partially hepatectomized mice
King et al., Endocrinology 1995
:
Dexamethasone does not inhibit induction of tyrosyl phosphorylation of ERK proteins by epidermal growth factor or phorbol myristate acetate, nor does it block induction of tyrosyl phosphorylation of Stat3/APRF by leukemia inhibitory factor or
interleukin-6 , or
induction of
JAK2 by leukemia inhibitory factor or interferon-gamma
Xu et al., J Clin Invest 1995
(Cell Transformation, Viral) :
Phosphorylation of
Jak2 in tax transformed cells
resulted from high expression of
IL-6
Berger et al., Blood 1997
(Multiple Myeloma) :
Prior treatment of U266 cells with IFN-beta downregulated
IL-6 induced tyrosine phosphorylation of gp130,
Jak2 , PTP1D/Syp, Shc, and Erk2, and GTP loading of p21ras
Faris et al., Immunology 1997
:
We have previously shown that
IL-6 induces activation of JAK1 and
JAK2 in human B cell lines
Leven et al., Blood Cells Mol Dis 1997
:
Studies on protein phosphorylation revealed that
IL6 , but not TPO,
stimulated phosphorylation of JAK1,
JAK2 and MAP kinase ... Studies on protein phosphorylation revealed that
IL6 , but not TPO,
stimulated phosphorylation of JAK1,
JAK2 and MAP kinase
Sengupta et al., Proc Natl Acad Sci U S A 1998
:
These results demonstrate an ERK mediated mechanism for inhibiting
IL-6 induced
Jak-STAT signaling that is rapid and inducible, and thus differs from previously described mechanisms for downmodulation of the Jak-STAT pathway