Interleukin-6 family signaling (Homo sapiens)
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Description
The interleukin-6 (IL6) family of cytokines includes IL6, IL11, IL27, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 and 2 (CT-1) and cardiotrophin-like cytokine (CLC) (Heinrich et al. 2003, Pflanz et al. 2002). The latest addition to this family is IL31, discovered in 2004 (Dillon et al. 2004). The family is defined largely by the shared use of the common signal transducing receptor Interleukin-6 receptor subunit beta (IL6ST, gp130). The IL31 receptor uniquely does not include this subunit, instead it uses the related IL31RA. The members of the IL6 family share very low sequence homology but are structurally highly related, forming anti-parallel four-helix bundles with a characteristic “up-up-down-down� topology (Rozwarski et al. 1994, Cornelissen et al. 2012).
Although each member of the IL6 family signals through a distinct receptor complex, their underlying signaling mechanisms are similar. Assembly of the receptor complex is followed by activation of receptor-associated Janus kinases (JAKs), believed to be constitutively associated with the receptor subunits.Activation of JAKs initiates downstream cytoplasmic signaling cascades that involve recruitment and phosphorylation of transcription factors of the Signal transducer and activator of transcription (STAT) family, which dimerize and translocate to the nucleus where they bind enhancer elements of target genes leading to transcriptional activation (Nakashima & Taga 1998).
Negative regulators of IL6 signaling include Suppressor of cytokine signals (SOCS) family members and PTPN11 (SHP-2).
IL6 is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep.
IL6 and IL11 bind their corresponding specific receptors IL6R and IL11R respectively, resulting in dimeric complexes that subsequently associate with IL6ST, leading to IL6ST homodimer formation (in a hexameric or higher order complex) and signal initiation. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL6 activities
LIF, CNTF, OSM, CTF1, CRLF1 and CLCF1 signal via IL6ST:LIFR heterodimeric receptor complexes (Taga & Kishimoto 1997, Mousa & Bakhiet 2013). OSM signals via a receptor complex consisting of IL6ST and OSMR. These cytokines play important roles in the regulation of complex cellular processes such as gene activation, proliferation and differentiation (Heinrich et al. 1998).
Antibodies have been developed to inhibit IL6 activity for the treatment of inflammatory diseases (Kopf et al. 2010). View original pathway at:Reactome.
Although each member of the IL6 family signals through a distinct receptor complex, their underlying signaling mechanisms are similar. Assembly of the receptor complex is followed by activation of receptor-associated Janus kinases (JAKs), believed to be constitutively associated with the receptor subunits.Activation of JAKs initiates downstream cytoplasmic signaling cascades that involve recruitment and phosphorylation of transcription factors of the Signal transducer and activator of transcription (STAT) family, which dimerize and translocate to the nucleus where they bind enhancer elements of target genes leading to transcriptional activation (Nakashima & Taga 1998).
Negative regulators of IL6 signaling include Suppressor of cytokine signals (SOCS) family members and PTPN11 (SHP-2).
IL6 is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep.
IL6 and IL11 bind their corresponding specific receptors IL6R and IL11R respectively, resulting in dimeric complexes that subsequently associate with IL6ST, leading to IL6ST homodimer formation (in a hexameric or higher order complex) and signal initiation. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL6 activities
LIF, CNTF, OSM, CTF1, CRLF1 and CLCF1 signal via IL6ST:LIFR heterodimeric receptor complexes (Taga & Kishimoto 1997, Mousa & Bakhiet 2013). OSM signals via a receptor complex consisting of IL6ST and OSMR. These cytokines play important roles in the regulation of complex cellular processes such as gene activation, proliferation and differentiation (Heinrich et al. 1998).
Antibodies have been developed to inhibit IL6 activity for the treatment of inflammatory diseases (Kopf et al. 2010). View original pathway at:Reactome.
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DataNodes
hexamer:Activated
JAKsphosphorylated hexameric IL-6 receptor:Activated
JAKs:p-Y546,Y584-PTPN11phosphorylated IL6 receptor hexamer:Activated
JAKs:Tyrosine/serine phosphorylated STAT1/3phosphorylated IL6 receptor hexamer:Activated
JAKs:PTPN11:CBLphosphorylated IL6 receptor hexamer:Activated
JAKs:PTPN11phosphorylated IL6 receptor hexamer:Activated
JAKs:SOCS3phosphorylated IL6 receptor hexamer:Activated
JAKs:STAT1,STAT3phosphorylated IL6 receptor hexamer:Activated JAKs:Tyrosine phosphorylated
STAT1,STAT3phosphorylated IL6 receptor hexamer:Activated
JAKsdimer,p-Y705-STAT3
dimer,p-Y701-STAT1:p-Y705-STAT3Annotated Interactions
hexamer:Activated
JAKshexamer:Activated
JAKsphosphorylated hexameric IL-6 receptor:Activated
JAKs:p-Y546,Y584-PTPN11IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in its K63-linked polyubiquitination. This stimulation-dependent ubiquitination was mediated by CBL, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner. IL-6 induced a rapid translocation of gp130 from the cell surface to endosomal compartments. The vesicular sorting molecule Hrs contributed to the lysosomal degradation of gp130 by directly recognizing its ubiquitinated form. Deficiency of either Hrs or CBL suppressed gp130 degradation, leading to a prolonged and amplified IL-6 signal.
There is a consensus that PTPN11 is involved in IL6-induced activation of the MAPK pathway but the molecular details are uncertain, in particular it is not clear whether the phosphatase activity of PTPN11 is required. Two pathways have been linked with activation of MAPK. One proposed mechanism is that PTPN11 acts as an adaptor for Growth factor receptor-bound protein 2-Son of sevenless homolog 1 (GRB2-SOS1) recruitment (Fukada et al. 1996, Kim & Baumann 1999). Kim & Baumann demonstrate IL6 induced PTPN11 recruitment to p-Tyr-759 of IL6ST but note that relatively little of the PTPN11 remains associated with IL6ST, suggesting that PTPN11 dissociates from the receptors when phosphorylated. This seems inconsistent with a GRB2:SOS1 recruitment role for PTPN11, though it is possible that only low levels or transient recruitment are required. Kim & Baumann demonstrated that IL6 induced ERK activation was not inhibited in cells transfected with a phosphatase inactive mutant of PTPN11, whereas a PTPN11 mutant missing the GRB2 interaction region significantly suppressed ERK activation. This suggests that phosphatase activity is not required for ERK activation while PTPN11 interaction with GRB2 is important. However, overexpression studies can generate artefactual interactions and this interpretation has been questioned (Dance et al. 2008). PTPN11 and the adaptor protein GRB2-associated-binding protein 1 (GAB1) have been reported to couple IL6ST signalling to ERK activation. In this proposal phosphorylated PTPN11 dissociates from IL6ST and becomes associated with membrane associated GAB1 in a complex with PI3-kinases (Takahashi-Tezuka et al. 1998, Eulenfeld & Schaper 2009). PTPN11 interaction is suggested to induce a conformational change in GAB1 that permits GAB1-PI3-kinase activation and enhancement of IL6-induced ERK pathway activation. However this is speculative, the role of PTPN11 phosphatase function is unclear. Other possible mechanisms are outlined by Dance et al. (2008), extrapolated from growth factor receptor mechanisms but with unknown relevance to IL6 and its interaction with IL6ST.
phosphorylated IL6 receptor hexamer:Activated
JAKs:Tyrosine/serine phosphorylated STAT1/3phosphorylated IL6 receptor hexamer:Activated
JAKs:PTPN11:CBLphosphorylated IL6 receptor hexamer:Activated
JAKs:PTPN11phosphorylated IL6 receptor hexamer:Activated
JAKs:PTPN11phosphorylated IL6 receptor hexamer:Activated
JAKs:PTPN11phosphorylated IL6 receptor hexamer:Activated
JAKs:PTPN11phosphorylated IL6 receptor hexamer:Activated
JAKs:SOCS3phosphorylated IL6 receptor hexamer:Activated
JAKs:SOCS3phosphorylated IL6 receptor hexamer:Activated
JAKs:STAT1,STAT3phosphorylated IL6 receptor hexamer:Activated
JAKs:STAT1,STAT3phosphorylated IL6 receptor hexamer:Activated
JAKs:STAT1,STAT3phosphorylated IL6 receptor hexamer:Activated JAKs:Tyrosine phosphorylated
STAT1,STAT3phosphorylated IL6 receptor hexamer:Activated JAKs:Tyrosine phosphorylated
STAT1,STAT3phosphorylated IL6 receptor hexamer:Activated JAKs:Tyrosine phosphorylated
STAT1,STAT3phosphorylated IL6 receptor hexamer:Activated
JAKsphosphorylated IL6 receptor hexamer:Activated
JAKsphosphorylated IL6 receptor hexamer:Activated
JAKsphosphorylated IL6 receptor hexamer:Activated
JAKsphosphorylated IL6 receptor hexamer:Activated
JAKsdimer,p-Y705-STAT3
dimer,p-Y701-STAT1:p-Y705-STAT3dimer,p-Y705-STAT3
dimer,p-Y701-STAT1:p-Y705-STAT3