The interleukin 20 (IL20) subfamily comprises IL19, IL20, IL22, IL24 and IL26. They are members of the larger IL10 family, but have been grouped together based on their usage of common receptor subunits and similarities in their target cell profiles and biological functions. Members of the IL20 subfamily facilitate the communication between leukocytes and epithelial cells, thereby enhancing innate defence mechanisms and tissue repair processes at epithelial surfaces. Much of the understanding of this group of cytokines is based on IL22, which is the most studied member (Rutz et al. 2014, Akdis M et al. 2016, Longsdon et al. 2012).
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The receptor chains are also utilized by multiple cytokines (Fig. 1)1,2. IL-12 signals via IL12Rβ1 and IL12Rβ248,71,72, while IL-23 signals through IL12Rβ1 and IL23R69,73. In contrast, IL-27 utilizes gp130 and WSX-174, while IL-35 signals via gp130 and IL12Rβ228. IL-35 is unusual in that it can also signals via two additional receptor chain compositions; gp130-gp130 and IL12Rβ2-lL12Rβ2 homodimers28. Signaling via all of these receptors is mediated by members of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) family27,75,76 (Fig. 1). JAK2 and either JAK1 or TYK2 appear to mediate phosphorylation of the IL-12 cytokine receptors family-associated STATs. IL-12 mediates signaling via pSTAT477, IL-23 via pSTAT3 and pSTAT469,73, IL-27 via pSTAT1 and pSTAT378,79, and IL-35 via pSTAT1 and pSTAT428. For IL-35, formation of a STAT1:STAT4 heterodimer is required for Ebi2/ Il12a transcription, but partially dispensable for supression28 (PMID:22814351)
Temporal models suggest that the first event in IL22 receptor formation is binding of Interleukin-22 (IL22) to IL22RA1), which pre associates with JAK1 (Li et al. 2004, Jones et al. 2008, Xie et al. 2000, Xu et al. 2001). The Interleukin-22 receptor consists of IL22RA1 and Interleukin-10 receptor subunit beta (IL10RB), which is also a component of the receptors for Interleukin-10 (IL10), Interleukin-22 (IL22), Interleukin-26 (IL26), Interleukin-28 (IL28), and Interferon lambda-1 (IFNL1).
Interferon lambda-1 (IFNL1) binds Interleukin-10 receptor subunit beta (IL10RB), which is associated with Non-receptor tyrosine-protein kinase TYK2 (TYK2), and Interferon lambda receptor-1 (IFNLR1), which is associated with Tyrosine-protein kinase JAK1 (JAK1). Interferon lambda-2 (IFNL2, IL28A), Interleukin-28B (IL28B, Interferon lambda-3) and Interferon lambda-1 (IFNL1, Interleukin-29) are related cytokines, collectively known as the type III interferons. They are distantly related to the type I interferons (IFNs) and are members of the class II cytokine family, which includes type I, II, and III interferons and the Interleukin-10 family (IL10, Interleukin-19 (IL19), Interleukin-20 (IL20), Interleukin-22 (IL22), Interleukin-24 (IL24), and Interleukin-26 (IL26)). They are encoded by genes that form a cluster on 19q13. Expression of all three IFNLs can be induced by viral infection. They share a heterodimeric class II cytokine receptor that consists of IFNLR1 and interleukin-10 receptor beta (IL10RB) (Kotenko et al. 2003, Sheppard et al. 2003). IL10RB is also part of the receptor complexes for IL10, IL22, IL24 and IL26. IFNL1, IFNL2 and IFNL3, like type I IFNs, can signal through ISRE regulatory sites and are likely to provide antiviral activity by the induction of at least a subset of IFN-stimulated genes (Dumoutier et al. 2004, Gad et al 2004, Sheppard et al. 2003).
Interleukin-24 (IL24) (and Interleukin-20 (IL20)) can activate a complex that consists of Interleukin-22 receptor subunit alpha-1 (IL22RA1), which is associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor B (IL20RB) (Dumoutier et al. 2001, Parrish-Novak et al. 2002). As it is not clear whether the receptor can form in the absence of ligand, association of the ligand with the receptor trimer is represented here as an uncertain event.
Interleukin-19 (IL19) binds a heterodimeric receptor complex that consists of Interleukin-20 Receptor subunit alpha (IL20RA) associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB). Interleukin-20 receptor A (IL20RA) and Interleukin-20 receptor B (IL20RB) form a receptor complex for Interleukin-19 (IL19) (and Interleukin-20 (IL20) and Interleukin-24 (IL24)) (Gallagher et al. 2000, Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014, Pletnev et al. 2003). This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand.
Interleukin-22 receptor subunit alpha-2 (IL22RA2), also known as Interleukin-22 binding protein (IL22BP), is a soluble receptor that binds Interleukin-22 (IL22) within the extracellular region, preventing IL22 from binding to the functional membrane-associated IL22 receptor (Xu et al. 2001, De Moura et al. 2009, Dumoutier et al. 2001, Kotenko et al. 2001). This may play a regulatory role in inflammation.
Interleukin-20 receptor A (IL20RA) binds to Interleukin-20 receptor B (IL20RB) (Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014, Dumoutier et al. 2001). This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand.
The classical model of JAK-STAT signaling suggests that phosphorylated Signal transducer and activator of transcription 3 (STAT3) translocates to the nucleus (Akira et al. 1994) where it binds DNA to mediate the effects of Interleukin-10 (IL10) on expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, with important consequences for their ability to activate and sustain immune and inflammatory responses. STAT3 is able to shuttle freely between the cytoplasm and the nucleus, independent of tyrosine phosphorylation (Liu et al. 2005, Li 2008, Reich 2013). Binding of unphosphorylated STAT3 to DNA has been reported (Nkansah et al. 2013). As it is not clear what triggers nuclear accumulation of STAT3 in response to IL10 this event is shown as an uncertain process.
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) dimerizes after dissociating from the interleukin-19 (IL19) receptor complex (Akira et al. 1994) or Interleukin-22 (IL22) receptor complex (Lagos-Quintana et al. 2003, Sestito et al. 2011).
According to the classical model, phosphorylated Signal transducer and activator of transcription (STAT) monomers associate in an active dimer form, which is stabilized by the reciprocal interactions between a phosphorylated tyrosine residue of one and the SH2 domain of the other monomer (Shuai et al. 1994). These dimers then translocate to the nucleus (Akira et al. 1994). Recently an increasing number of studies have demonstrated the existence of STAT dimers in unstimulated cell states and the capability of STATs to exert biological functions independently of phosphorylation (Braunstein et al. 2003, Li et al. 2008, Santos & Costas-Pereira 2011). As phosphorylation of STATs is not unequivocally required for its subsequent translocation to the nucleus, this event is shown as an uncertain process.
Temporal models suggest that binding of Interleukin‑22 (IL22) to Interleukin‑22 receptor subunit alpha 1 (IL22RA1) creates a surface that is bound by the extracellular region of Interleukin‑10 receptor beta chain (IL10RB) (Li et al. 2004, Bleicher et al. 2008).
Signal transducer and activator of transcription 3 (STAT3) is believed to dissociate from the Interleukin-19 (IL19) receptor complex after phosphorylation. The Interleukin-19 receptor complex is formed by Interleukin-20 receptor A (IL20RA) associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor B (IL20RB). This is a black box event because dissociation of STAT3 from the IL19 receptor is inferred from IL-19 induced changed in STA3 regulated gene expression (Tian et al. 2008).
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated after Interleukin-19 (IL19) binds its receptor complex (Dumoutier et al. 2001, Tian et al. 2008, Jain et al.2011). The receptor complex consists of IL19, Interleukin-20 receptor subunit alpha (IL20RA), phosphorylated Tyrosine-protein kinase JAK1 (JAK1), Interleukin-20 receptor beta (IL20RB) and STAT3.
Signal transducer and activator of transcription 3 (STAT3) is believed to bind the Interleukin-19 (IL19) /Interleukin-19 receptor complex. IL19 stimulates transient STAT3 phosphorylation and translocation from the cytoplasm to the nucleus (Dumoutier et al. 2001, Tian et al. 2008, Jain et al.2011). STAT3 binding is inferred to be a prerequisite for its phosphorylation from the signaling mechanism of the related interleukin-10 receptor, which is able to bind and phosphorylate STAT3 (Riley et al. 1999). The IL19 receptor complex consists of Interleukin-20 Receptor A (IL20RA) associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor B (IL20RB). This is a black box event because binding of STAT3 after IL19 stimulus has not been demonstrated.
Interleukin 26 is believed to bind to its receptor complex which is formed by Interleukin 20 receptor subunit alpha and JAK1 (Yoon et al. 2006, Yoon et al. 2010, Sheikh et al. 2004). This is a black box event because constitutive pre association of JAK1 with IL20RA is inferred from the observation that IL20RA belongs to the cytokine receptor type II family, which has a common domain necessary for binding of JAK1 and release signaling (Ferrao et al. 2016, Hor et al. 2004).
The interaction of Interleukin-26 (IL26) with Interleukin-20 receptor subunit alpha (IL20RA) induces conformational changes that allow it to bind Interleukin-10 receptor subunit beta (IL10RB) (Yoon et al. 2006, 2010), which is pre associated with Non-receptor tyrosine-protein kinase TYK2 (TYK2) (another citation).
Interleukin-24 (IL24) binds a receptor complex containing Interleukin-20 Receptor subunit alpha (IL20RA) associated with Tyrosine-protein kinase JAK1 (JAK1) (Andoh et al. 2009, Logsdon et al. 2012) and Interleukin-20 receptor subunit beta (IL20RB) (Parrish Novak et al.1998). Furthermore IL24 can also bind Interleukin-22 receptor subunit alpha-1 (IL22RA1) and IL20RB (Wang et al. 2002) to form a ligand receptor complex. As it is not clear whether the receptor complex can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
IFNL1 can induce phosphorylation of Signal transducer and activator of transcription 1 alpha/beta (STAT1), Signal transducer and activator of transcription 3 (STAT2), Signal transducer and activator of transcription 3 (STAT3), Signal transducer and activator of transcription 4 (STAT4) and Signal transducer and activator of transcription 5 (STAT5) (Dumoutier et al. 2004, Novak et al. 2008, Dickensheets et al. 2013) via stimulation of the Interferon lambda-1 (IFNL1) receptor complex. This complex consists of IFNL1, IFNLR1, which is associated with phosphorylated Tyrosine-protein kinase JAK1 (JAK1), Interleukin-10 receptor beta (IL10RB), which is associated with phosphorylated Non-receptor tyrosine-protein kinase TYK2 (TYK2) and STAT1. This is a black-box event because direct evidence for STAT4 and 5 binding and activation is lacking (Jordan et al. 2007).
Tyrosine-protein kinase JAK1 (JAK1) and Non-receptor tyrosine-protein kinase TYK2 (TYK2) are believed to be phosphorylated after Interleukin-26 (IL26) ligand/receptor interaction. The Interleukin-10 receptor subunit beta (IL10RB) component of the IL26 receptor is also a component of the IL10 receptor, where it associates with TYK2 (Finbloom & Winestock 1995). The Interleukin-20 receptor subunit alpha (IL20RA) component of the IL26 receptor, like the Interleukin-10 receptor subunit alpha (IL10RA) subunit of the IL10 receptor, is a type II cytokine receptor, suggested by homology with IL10RA to be capable of binding JAK1 (Ferrao et al. 2016). Structural models of the IL10 receptor suggest that the space between the two receptor subunits is occupied by JAK1 and TYK2 (Yoon et al. 2006, 2010). Taken together, these observations suggest that IL26 receptor signaling involves JAK1 and TYK2 activation.
Interleukin-22 receptor subunit alpha-1 (IL22RA1) is phosphorylated within the receptor complex, which consists of Interleukin-22 (IL22), IL22RA1 associated with phosphorylated Tyrosine protein kinase JAK1 (JAK1) and Interleukin-10 receptor subunit beta (IL10RB) associated with phosphorylated non-receptor tyrosine-protein kinase TYK2 (TYK2). IL22 stimulated IL22RA1 tyrosine phosphorylation and recruitment of Tyrosine protein phosphatase non receptor type 11 (PTPN11, SHP2). PTPN11 binding was abolished by mutation of Tyrosines-251 and 301 (Meng et al. 2010). This is a black-box event because it is not clear which kinase is responsible for IL22RA1 phosphorylation.
Signal transducer and activator of transcription 1alpha/beta (STAT1) is believed to dimerize after it dissociates from the Interleukin-24 (IL24) receptor complex. This is a black box event because dimerization is inferred from STAT1 dimerization in response to Interferon gamma (IFNG) (Wehinger et al. 1996) and the observed translocation of STAT1 to the nucleus in response to IL24 (Parrish-Novak et al. 2002).
Tyrosine-protein kinase JAK1 (JAK1) is phosphorylated after Interleukin-24 (IL24) ligand interaction with its receptor. There are two IL24 receptors. One consists of Interleukin-20 receptor subunit alpha (IL20RA), Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB), the other, represented in this event, uses interleukin-22 receptor subunit alpha-1 (IL22RA1) instead of IL20RA (Dumoutier et al. 2001, Wang et al. 2002). IL22RA1 can bind JAK1 (Ferrao et al. 2016). IL24 can stimulate JAK1 phosphorylation in human colonic subepithelial myofibroblasts, where the components of both forms of the IL24 receptor are expressed (Andoh et al. 2009). It has been demonstrated that both forms of the IL24 receptor can activate STAT3 (Dumoutier et al. 2001, Wang et al. 2002). Based on the consensus understanding of JAK/STAT signaling, STAT3 activation is very likely to be preceded by JAK1 phosphorylation and it is therefore likely that JAK1 is phosphorylated in both forms of the IL24 receptor. This is a black box event because it has not been established that both forms of the IL24 receptor are involved in JAK1 phosphorylation.
Signal transducer and activator of transcription 3 (STAT3) is believed to bind the Interleukin-22 (IL22) receptor complex, which consists of IL22, phosphorylated Interleukin-22 receptor subunit alpha-1 (IL22RA1), phosphorylated Tyrosine-protein kinase JAK1 (JAK1), Interleukin-10 receptor subunit beta (IL10RB), phosphorylated Non-receptor tyrosine-protein kinase TYK2 (TYK2) and Tyrosine-protein phosphatase non-receptor type 11 (PTPN11 or SHP2) (Meng et al. 2010, Sestito et al. 2011). STAT3 has been reported to pre-associate with IL22RA in the absence of phosphorylated receptor tyrosines (Dumoutier et al. 2009). This is a black box event because STAT3 binding is represented here as a post-receptor phosphorylation event, inferred from the consensus on interleukin receptor JAK-STAT signaling (Li et al. 2008, Santos et al. 2011).
Interleukin-20 (IL20) binds a heterodimeric receptor complex that consists of Interleukin-20 receptor subunit alpha (IL20RA), which is associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB) (Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014). Interleukin-20 receptor A (IL20RA) and Interleukin-20 receptor B (IL20RB) form a receptor complex for Interleukin-20 (IL20), Interleukin-19 (IL19) and Interleukin-24 (IL24) (Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014). IL20 can also bind a receptor complex that consists of Interleukin-22 receptor subunit alpha-1 (IL22RA1) and IL20RB (Kolumam et al. 2017). As it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain black box event.
Phosphorylated Signal transducer and activator of transcription 1 alpha/beta (STAT1), Phosphorylated Signal transducer and activator of transcription 2 (STAT2) , Phosphorylated Signal transducer and activator of transcription 3 (STAT3) , Phosphorylated Signal transducer and activator of transcription 4 (STAT4) and Phosphorylated Signal transducer and activator of transcription 5 (STAT5) are believed to dissociate from the receptor complex (Dumoutier et al. 2004, Novak et al. 2008). This is a black-box event because dissociation is inferred from other interleukin signaling cascades such as Interleukin-10 (Niemand et al. 2003, Braum et al. 2013, Xiong et al. 2014, Sheikh et al. 2006, You et al. 2013) where dissociation occurs before STAT dimerization and translocation to the nucleus.
Tyrosine protein kinase JAK1 (JAK1) binds Interleukin-20 receptor subunit alpha (IL20RA). JAK1 coimmunoprecipitates with several class II receptor complexes including Interferon gamma receptor 1 (IFNGR1), Interferon alpha/beta receptor 2 (IFNAR2), Interferon lambda receptor 1 (IFNLR1), Interleukin-10 receptor subunit alpha (IL10RA), Interleukin-22 receptor subunit alpha 1 (IL22RA1) and Interleukin-20 receptor subunit alpha (IL20RA), leading to the suggestion that Class II receptors may have a common sequence motif for JAK recognition (Ferrao et al. 2016). This is a black box event because JAK1 binding to IL20RA is inferred from binding to related receptors and subsequent JAK/STAT signaling events (Ferrao et al 2016, Hann et al. 2006, Murakami et al. 1991).
Interferon lambda receptor 1 receptor (IFNLR1, IL28RA) is believed to be phosphorylated by the Interferon lambda-1 (IFNL1 or IL29) complex (Sheppard et al. 2003). This complex is formed by IFNL1, IFNLR1, which is associated with phosphorylated Tyrosine protein kinase JAK1 (JAK1) and Interleukin 10 receptor beta (IL10RB), which is associated with phosphorylated Non-receptor tyrosine-protein kinase TYK2 (TYK2). IFNL1 induced Signal transducer and activator of transcription 2 (STAT2) tyrosine phosphorylation but not that of other STATs is at least partly mediated by IFNLR1 tyrosines 343 and 517 (Dumoutier et al. 2004). This is a black box event because there is not enough evidence to associate specific tyrosines with the binding of STATs and because the phosphorylation of these tyrosines is inferred from the STAT signaling mechanisms of related receptors.
Inferred from rat, mouse, human :Tyrosine protein kinase JAK1 (JAK1) and Non-receptor tyrosine-protein kinase TYK2 (TYK2) are believed to be phosphorylated after Interleukin-22 interacts with its receptor. The receptor is a complex formed by Interleukin-22 receptor subunit alpha-1 (IL22RA1), JAK1, Interleukin-10 receptor subunit beta (IL10RB) and TYK2 (Lejeune et al. 2002, Sabat et al. 2014).
This is a black-box event because the JAK1/TYK2 coordinates phosphorylated after IL22 stimulus are unknown.
Tyrosine protein kinase JAK1 (JAK1) binds to Interleukin-22 receptor subunit alpha 1 (IL22RA1). IL22RA1 was identified as one of several interleukin receptors able to bind JAK1 in coimmunoprecipitation experiments (Ferrao et al. 2016).
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) dimer translocates from the cytosol to the nucleoplasm after Interleukin-24 (IL24) stimulus (in BHK570 cells). Signal transducer and activator of transcription 1 alpha/beta (STAT1) was also translocated but only at high Interleukin-20 (IL20) doses (Parrish-Novak et al. 2002). This is a black box event because the mechanism of translocation is not fully represented and may not require STAT3 dimer formation, but it can be inferred from the pattern of other Interleukins as IL10 signaling cascade (Niemand et al. 2003).
Signal transducer and activator of transcription 3 (STAT3) is believed to bind the Interleukin-24 (IL24) receptor complex (Parrish Novak et al. 2002, Wang et al. 2002, Andoh et al. 2009). There are two forms of the IL24 receptor. The receptor complex represented here consists of IL24, Interleukin 22 receptor subunit alpha 1 (IL22RA1), phosphorylated Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB). Both forms of the IL24 receptor can activate STAT3 (Dumoutier et al. 2001, Wang et al. 2002). Based on the consensus understanding of JAK/STAT signaling, STAT3 activation is very likely to be preceded by STAT3 binding to the IL24 receptor.
This is a black box event because STAT3 binding is inferred as a prerequisite for STAT3 phosphorylation, based on STAT3 binding by the related IL10 receptor (Riley et al. 1999).
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by the Interleukin-22 (IL22) receptor complex (Lejeune et al. 2002, Dumoutier et al. 2009, Lindemanns et al. 2015), which consists of IL22, phosphorylated Interleukin-22 receptor subunit alpha-1 (IL22RA1), phosphorylated Tyrosine-protein kinase JAK1 (JAK1), Interleukin-10 receptor subunit beta (IL10RB), phosphorylated Non-receptor tyrosine-protein kinase TYK2 (TYK2) and STAT3 (Meng et al. 2010, Sestito et al. 2011).
Signal transducer and activator of transcription 1 alpha/beta (STAT1) or Signal transducer and activator of transcription 3 (STAT3) are believed to bind the Interleukin-26 (IL26) receptor complex (You et al. 2013), which consists of IL26, Interleukin-10 receptor subunit beta (IL10RB), phosphorylated Non-receptor tyrosine-protein kinase TYK2 (TYK2), Interleukin-20 receptor subunit alpha (IL20RA) and phosphorylated Tyrosine-protein kinase JAK1 (JAK1) (Sheikh et al. 2004). This is a black box event since there is no direct evidence that STAT1 or STAT3 bind to the receptor complex before being phosphorylated but this can be inferred from the signaling mechanism of other related interleukin receptors such as IL10 (Weber-Nordt et al. 1996, Braum et al. 2013). JAK1 association can also be inferred from the presence of a JAK1 binding domain in IL20RA that has been demonstrated to be a JAK1 binding site in several related interleukin receptors including IL22RA1 and IL10RA (Ferrao et al. 2016).
Tyrosine-protein kinase JAK1 (JAK1) is believed to be phosphorylated after Interleukin-19 (IL19)/IL19 receptor interaction. The IL19 receptor complex is identical to one of the two Interleukin-24 (IL24) receptors ((Dumoutier et al. 2001, Wang et al. 2002). IL24 can stimulate JAK1 phosphorylation in human colonic subepithelial myofibroblasts, where the components of both forms of the IL24 receptor are expresed (Andoh et al. 2009). Although it was not established that both forms of the IL24 receptor were involved in JAK1 phosphorylation, it has been demonstrated that the IL19 receptor when stimulated with IL19 and both forms of the IL24 receptor when stimulated with IL24 can activate STAT3 (Dumoutier et al. 2001, Wang et al. 2002). Based on the consensus understanding of JAK/STAT signaling, STAT3 activation is very likely to be preceded by JAK1 phosphorylation and it is therefore likely that both forms of the IL24 receptor, including the form that is also a receptor for IL19, lead to JAK1 phosphorylation. This reaction is a black box event because there is no experimental data confirming JAK1 phosphorylation in response to IL19.
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated after binding to Interleukin-24 (IL24) activated receptor complex. This activated receptor complex is formed by IL24 ligand, Interleukin-22 receptor subunit alpha-1 (IL22RA1), phosphorylated Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB) (Parrish-Novak et al. 2002, Wang et al. 2002, Dumoutier et al. 2001). This is a black box event since the identity of the phosphorylated residues in STAT3 is unknown.
Signal transducer and activator of transcription 1 alpha/beta (STAT1) and Signal transducer and activator of transcription 3 (STAT3) are believed to bind the Interleukin-24 (IL24) receptor complex (Wang et al. 2002, Andoh et al. 2009, Parrish-Novak et al. 1998, Li et al. 2013). This is a black box event because STAT3 binding is inferred from other interleukin receptor ligand interactions where STAT3 activation is followed by a transient interaction with the receptor complex e.g.Interleukin-10 receptor (Weber-Nordt et al. 1996).
Signal transducer and activator of transcription 3 (STAT3)and STAT5 are believed to bind the receptor complex following the phosphorylation of JAK2 and JAK3 within the IL20:IL20RA receptor complex, because Interleukin-20 (IL20) stimulation leads to STAT3 nuclear translocation (Blumberg et al. 2001, Parrish-Novak et a. 2002)). Phosphorylation of STAT5 at Tyr-694 has been observed in response to IL20 but it is not clear which IL20 receptor was involved (Tritsaris et al. 2007). This is a black box event because there is no direct evidence of STAT3 or STAT5 binding, which is inferred to be a prerequisite for STAT phosphorylation in response to IL20.
Interferon lambda-1 (IFNL1) binds Interleukin-10 receptor subunit beta (IL10RB), which is associated with Non-receptor tyrosine-protein kinase TYK2 (TYK2), and Interferon lambda receptor-1 (IFNLR1), which is associated with Tyrosine-protein kinase JAK1 (JAK1). Interferon lambda-2 (IFNL2, IL28A), Interleukin-28B (IL28B, Interferon lambda-3) and Interferon lambda-1 (IFNL1, Interleukin-29) are related cytokines, collectively known as the type III interferons. They are distantly related to the type I interferons (IFNs) and are members of the class II cytokine family, which includes type I, II, and III interferons and the Interleukin-10 family (IL10, Interleukin-19 (IL19), Interleukin-20 (IL20), Interleukin-22 (IL22), Interleukin-24 (IL24), and Interleukin-26 (IL26)). They are encoded by genes that form a cluster on 19q13. Expression of all three IFNLs can be induced by viral infection. They share a heterodimeric class II cytokine receptor that consists of IFNLR1 and interleukin-10 receptor beta (IL10RB) (Kotenko et al. 2003, Sheppard et al. 2003). IL10RB is also part of the receptor complexes for IL10, IL22, IL24 and IL26. IFNL1, IFNL2 and IFNL3, like type I IFNs, can signal through ISRE regulatory sites and are likely to provide antiviral activity by the induction of at least a subset of IFN-stimulated genes (Dumoutier et al. 2004, Gad et al 2004, Sheppard et al. 2003).
Tyrosine protein kinase JAK1 (JAK1) binds Interferon lambda receptor 1 (IFNLR1). The Box1 of IFNLR1 binds to the F2 subdomain of the JAK1 FERM, in a cleft formed by helices F2 alpha2, F2 alpha3, and F2 alpha4 (Ferrao et al. 2017).
Tyrosine-protein kinase JAK1 (JAK1) is phosphorylated after Interleukin-24 (IL24) ligand interaction with its receptor. There are two IL24 receptors. One consists of Interleukin-20 receptor subunit alpha (IL20RA), Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB), the other uses nterleukin-22 receptor subunit alpha-1 (IL22RA1) instead of IL20RA (Dumoutier et al. 2001, Wang et al. 2002). IL24 can stimulate JAK1 phosphorylation in human colonic subepithelial myofibroblasts, where the components of both forms of the IL24 receptor are expresed (Andoh et al. 2009). It has been demonstrated that both forms of the IL24 receptor can activate STAT3 (Dumoutier et al. 2001, Wang et al. 2002). Based on the consensus understanding of JAK/STAT signaling, STAT3 activation is very likely to be preceded by JAK1 phosphorylation and it is therefore likely that JAK1 is phosphorylated in both forms of the IL24 receptor.
This is a black box event because it has not been established that both forms of the IL24 receptor are involved in JAK1 phosphorylation.
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2) binds the Interleukin-22 (IL22) receptor complex. Tyrosines 251 and 301 of IL22RA1 are required for PTPN11 binding (Meng et al. 2010).
Signal transducer and activator of transcription 5A and 5B (STAT5A, STAT5B) is phosphorylated after binding the Interleukin-20 (IL20) receptor complex, which consist of IL20, Interleukin-20 receptor subunit alpha (IL20RA), phosphorylated Tyrosine-protein kinase JAK1 (JAK1), Interleukin-20 receptor subunit beta (IL20RB), phosphorylated Tyrosine-protein kinase JAK2 (JAK2), Tyrosine-protein kinase JAK3 (JAK3) and STAT5. After IL20 stimulation STAT5 is phosphorylated at Tyr-694 (Tritsaris et al. 2007). It is not clear which kinase subunit of the receptor complex is responsible for STAT5 phosphorylation.
Signal transducer and activator of transcription 1 alpha/beta (STAT1) and Signal transducer and activator of transcription 3 (STAT3) are believed to be phosphorylated after binding the Interleukin-24 (IL24) receptor complex (Parrish Novak et al. 1998, Andoh et al. 2009, Wang et al. 2002). This complex consists of IL24 ligand, phosphorylated Interleukin-20 receptor subunit alpha (IL20RA), phosphorylated Tyrosine-protein kinase JAK1 (JAK1), Interleukin-20 receptor subunit beta (IL20RB) and STAT1 or STAT3 . This is a black box event because STAT binding is inferred to precede STAT phosphorylation.
Phosphorylated Signal transducer and activator of transcription 5A or 5B (STAT5) dissociates from the Interleukin-20 (IL20) receptor complex (Tristaris et al. 2007). This is a black box event because dissociation is inferred from the signalling events of other Interleukins where phosphorylated STATs translocate to the nucleus, as with Interleukin-3 (Hirose et al. 2014).
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) dissociates from Interleukin-24 (IL24) activated receptor complex. This activated receptor complex is formed by IL24 ligand, Interleukin-22 receptor subunit alpha-1 (IL22RA1), phosphorylated Tyrosine-protein kinase JAK1 (JAK) and Interleukin-20 receptor subunit beta (IL20RB) (Parrish-Novak et al. 2002).
This is a black box event since there is no direct evidence of this dissociation but there is evidence dissociation occurs before translocation in other interleukin signaling cascades.
Tyrosine-protein kinase JAK2 (JAK2) or Tyrosine-protein kinase JAK3 (JAK3) are phosphorylated after the binding of Interleukin-20 (IL20) to a heterodimeric receptor complex formed by Interleukin-20 receptor subunit alpha (IL20RA) associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB). JAK2 is phosphorylated at Tyr-1007/1008 (Tritsaris et al. 2007). JAK3 is also phosphorylated (Lee et al. 2012). This is a black box event because it is unclear whether JAK2 and JAK3 are phosphorylated simultaneously or sequentially during IL20 stimulation.
Tyrosine-protein kinase JAK1 (JAK1) and Non-receptor tyrosine-protein kinase TYK2 (TYK2) are phosphorylated after Interferon lambda-1 (IFNL1, IL29) interacts with its receptor complex, which consists of Interferon lambda receptor-1 (IFNLR1 (class II cytokine receptor)), JAK1, Interleukin-10 receptor beta (IL10RB) and TYK2 (Novak et al.2008, Dumoitier et al. 2004).This initiates a signaling cascade that involves Jak1 and Tyk2 dependent tyrosine phosphorylation of signal transducers and activators of transcription 1 (STAT1) and STAT2 proteins that interact with a third protein, the p48 DNA binding subunit, to form the IFN stimulated gene factor 3 complex (ISGF3).
This is a black box event since direct evidence for JAK1 and TYK2 binding after IFNL1 stimulation is lacking. However, this can be inferred from other cytokine signaling. In other cytokine ligand receptor cascades such as IFNalpha signaling, STAT activation occurs after phosphorylation by kinases associated with the receptor (Sheppard et al. 2003).
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) is believed to dimerize after it dissociates from the Interleukin-24 (IL24) receptor complex. This is a black box event because dimerization is inferred from STAT3 dimerization in response to interleukin-10 (Niemand et al. 2003) and the observed translocation of STAT3 to the nucleus in response to IL24 (Parrish-Novak et al. 2002). In several other cytokine signalling cascades a phosphorylated dimer is necessary for binding to DNA and gene transcription (Park et al. 2000).
Signal transducer and activator of transcription 1 alpha/beta (STAT1) dimer translocates from the cytosol to the nucleus after Interleukin-24 stimulus (IL24) (in BHK cells bearing IL 20RA/IL 20RB) (Parrish Novak et al. 2007). This is a black box event because the mechanism by which this event occurs (diffusion, transport) is unknown (Darnell 1997).
Tyrosine-protein kinase JAK2 (JAK2) or Tyrosine-protein kinase JAK3 (JAK3) are believed to bind the complex formed by Interleukin-20 (IL20), Interleukin-20 Receptor subunit alpha (IL20RA), which is associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB). JAK2 was phosphorylated in response to IL20 in porcine aorta endothelial cells (Tritsaris et al. 2007). JAK2 and JAK3 were phosphorylated after IL20 stimulation of human 253J bladder cancer cells (Lee et al. 2012).
This is a black box event since it is unclear whether JAK2/3 are constitutively associated or bind to the receptor after IL20 stimulation.
Interleukin-10 receptor subunit beta (IL10RB, IL10R2) binds non-receptor tyrosine-protein kinase TYK2 (TYK2). Interleukin-10 receptor subunit alpha (IL10RA, IL10R1) and IL10RB extracellular domains bind Interleukin-10 (IL10), their intracellular domains are constitutively associated with Tyrosine-protein kinase JAK1 (JAK1) and TYK2 kinases, respectively (Finbloom & Winestock 1995, Ho et al. 1995). The function of the IL10RB Intracellular domain is to provide a docking site for TYK2, which provides a generic activation signal that can be used to activate signaling pathways associated with the four different Receptor 1 chains, Interleukin-20 receptor subunit alpha (IL20RA), Interleukin-22 receptor subunit alpha-1 (IL22RA1), Interferon lambda receptor 1 (IFNLR1) and Interleukin-10 receptor subunit alpha (IL10RA).
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 1 alpha/beta (STAT1) are believed to dissociate from the Interleukin-26 (IL26) receptor complex. This is a black-box event because dissociation is inferred from other interleukin signaling cascades, e.g. Interleukin-10 (Niemand et al. 2003, Braum et al. 2013, Xiong et al. 2014, Sheikh et al. 2006, You et al. 2013) where dissociation occurs before dimerization and translocation to the nucleus.
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) dissociates from the Interleukin-22 (IL22) receptor complex, which consists of IL22, phosphorylated Interleukin-22 receptor subunit alpha 1 (IL22RA1), phosphorylated Tyrosine-protein kinase JAK1 (JAK1), Interleukin-10 receptor subunit beta (IL10RB), phosphorylated Non-receptor tyrosine protein-kinase TYK2 (TYK2) and Tyrosine protein phosphatase non receptor type 11 (PTPN11 or SHP2) and STAT3. This is a black-box event because dissociation is inferred from other interleukin signaling cascades e.g. Interleukin-10 (Niemand et al. 2003, Braum et al. 2013, Xiong et al. 2014, Sheikh et al. 2006, You et al. 2013) where dissociation occurs before STAT dimerization and translocation to the nucleus.
Signal transducer and activator of transcription 1 alpha/beta (STAT1) or Signal transducer and activator of transcription 3 (STAT3) are believed to be phosphorylated by the Interleukin 26 (IL26) receptor complex,which consists of IL26, Interleukin-10 receptor subunit beta (IL10RB), phosphorylated Non-receptor tyrosine-protein kinase TYK2 (TYK2), Interleukin-20 receptor subunit alpha (IL20RA), phosphorylated Tyrosine-protein kinase JAK1 (JAK1) (Sheikh et al. 2004), STAT1 and STAT3. This is a black box event since there is no direct evidence that STAT1 or STAT3 bind the receptor complex before being phosphorylated, but this can be inferred from the signaling mechanism of other related interleukin receptors such as IL10 (Weber-Nordt et al. 1996, Braum et al. 2013).
IFNL1 can induce phosphorylation of Signal transducer and activator of transcription 1 alpha/beta (STAT1), Signal transducer and activator of transcription 2 (STAT2) , Signal transducer and activator of transcription 3 (STAT3) , Signal transducer and activator of transcription 4 (STAT4) ,Signal transducer and activator of transcription 5 (STAT5) (Dumoutier et al. 2004, Novak et al. 2008), Signal transducer and activator of transcription 2 (STAT2)(Dickensheets et al. 2013), Signal transducer and activator of transcription 4 (STAT4) and Signal transducer and activator of transcription 5 (STAT5) (Dumoutier et al. 2004).
This is a black-box event because direct evidence for STAT4 and 5-binding and activation is lacking. STAT binding is inferred from subsequent phosphorylation in response to IFNL1 (Jordan et al. 2007).
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 1 alpha/beta (STAT1) dissociate from the Interleukin-24 (IL24) receptor complex (Wang et al. 2002). This complex is formed by IL24 ligand, phosphorylated Interleukin-20 receptor subunit alpha (IL20RA), phosphorylated Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB) (Parrish-Novak et al. 2007). This is a black box event because dissociation is inferred to occur to allow STAT dimerization and translocation to the nucleus, as is the case for STAT3 activation by the Interleukin-10 receptor (Niemand et al. 2003).
Overexpression and production of Suppressor of cytokine signaling 3 (SOCS3) has been reported after Interleukin 24 (IL24) stimulus (Andoh et al. 2009, Uto-Konomi et al. 2012). This is a black box event since details about the binding to DNA, transcription and translation are omitted.
Interleukin-20 (IL20) (and Interleukin-24 (IL24)) can activate a complex that consists of Interleukin-22 receptor subunit alpha-1 (IL22RA1), which is associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor B (IL20RB) (Dumoutier et al. 2001, Parrish-Novak et al. 2002). As it is not clear whether the receptor can form in the absence of ligand, association of the ligand with the receptor trimer is represented here as an uncertain event.
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Signaling via all of these receptors is mediated by members of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) family27,75,76 (Fig. 1). JAK2 and either JAK1 or TYK2 appear to mediate phosphorylation of the IL-12 cytokine receptors family-associated STATs. IL-12 mediates signaling via pSTAT477, IL-23 via pSTAT3 and pSTAT469,73, IL-27 via pSTAT1 and pSTAT378,79, and IL-35 via pSTAT1 and pSTAT428. For IL-35, formation of a STAT1:STAT4 heterodimer is required for Ebi2/ Il12a transcription, but partially dispensable for supression28 (PMID:22814351)
p-STAT3,
p-STAT4,p-STAT5Annotated Interactions
The Interleukin-22 receptor consists of IL22RA1 and Interleukin-10 receptor subunit beta (IL10RB), which is also a component of the receptors for Interleukin-10 (IL10), Interleukin-22 (IL22), Interleukin-26 (IL26), Interleukin-28 (IL28), and Interferon lambda-1 (IFNL1).
Interleukin-20 receptor A (IL20RA) and Interleukin-20 receptor B (IL20RB) form a receptor complex for Interleukin-19 (IL19) (and Interleukin-20 (IL20) and Interleukin-24 (IL24)) (Gallagher et al. 2000, Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014, Pletnev et al. 2003).
This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand.
This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand.
According to the classical model, phosphorylated Signal transducer and activator of transcription (STAT) monomers associate in an active dimer form, which is stabilized by the reciprocal interactions between a phosphorylated tyrosine residue of one and the SH2 domain of the other monomer (Shuai et al. 1994). These dimers then translocate to the nucleus (Akira et al. 1994). Recently an increasing number of studies have demonstrated the existence of STAT dimers in unstimulated cell states and the capability of STATs to exert biological functions independently of phosphorylation (Braunstein et al. 2003, Li et al. 2008, Santos & Costas-Pereira 2011). As phosphorylation of STATs is not unequivocally required for its subsequent translocation to the nucleus, this event is shown as an uncertain process.
As it is not clear whether the receptor complex can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
This is a black-box event because direct evidence for STAT4 and 5 binding and activation is lacking (Jordan et al. 2007).
This is a black-box event because it is not clear which kinase is responsible for IL22RA1 phosphorylation.
This is a black box event because STAT3 binding is represented here as a post-receptor phosphorylation event, inferred from the consensus on interleukin receptor JAK-STAT signaling (Li et al. 2008, Santos et al. 2011).
This is a black box event because the mechanism of translocation is not fully represented and may not require STAT3 dimer formation, but it can be inferred from the pattern of other Interleukins as IL10 signaling cascade (Niemand et al. 2003).
This is a black box event because STAT3 binding is inferred as a prerequisite for STAT3 phosphorylation, based on STAT3 binding by the related IL10 receptor (Riley et al. 1999).
This is a black box event since there is no direct evidence that STAT1 or STAT3 bind to the receptor complex before being phosphorylated but this can be inferred from the signaling mechanism of other related interleukin receptors such as IL10 (Weber-Nordt et al. 1996, Braum et al. 2013). JAK1 association can also be inferred from the presence of a JAK1 binding domain in IL20RA that has been demonstrated to be a JAK1 binding site in several related interleukin receptors including IL22RA1 and IL10RA (Ferrao et al. 2016).
This is a black box event since the identity of the phosphorylated residues in STAT3 is unknown.
The Box1 of IFNLR1 binds to the F2 subdomain of the JAK1 FERM, in a cleft formed by helices F2 alpha2, F2 alpha3, and F2 alpha4 (Ferrao et al. 2017).
This is a black box event because it has not been established that both forms of the IL24 receptor are involved in JAK1 phosphorylation.
This is a black box event because STAT binding is inferred to precede STAT phosphorylation.
JAK2 is phosphorylated at Tyr-1007/1008 (Tritsaris et al. 2007). JAK3 is also phosphorylated (Lee et al. 2012).
This is a black box event because it is unclear whether JAK2 and JAK3 are phosphorylated simultaneously or sequentially during IL20 stimulation.
This is a black box event because dimerization is inferred from STAT3 dimerization in response to interleukin-10 (Niemand et al. 2003) and the observed translocation of STAT3 to the nucleus in response to IL24 (Parrish-Novak et al. 2002). In several other cytokine signalling cascades a phosphorylated dimer is necessary for binding to DNA and gene transcription (Park et al. 2000).
This is a black box event since it is unclear whether JAK2/3 are constitutively associated or bind to the receptor after IL20 stimulation.
The function of the IL10RB Intracellular domain is to provide a docking site for TYK2, which provides a generic activation signal that can be used to activate signaling pathways associated with the four different Receptor 1 chains, Interleukin-20 receptor subunit alpha (IL20RA), Interleukin-22 receptor subunit alpha-1 (IL22RA1), Interferon lambda receptor 1 (IFNLR1) and Interleukin-10 receptor subunit alpha (IL10RA).
This is a black box event since there is no direct evidence that STAT1 or STAT3 bind the receptor complex before being phosphorylated, but this can be inferred from the signaling mechanism of other related interleukin receptors such as IL10 (Weber-Nordt et al. 1996, Braum et al. 2013).
This is a black box event since details about the binding to DNA, transcription and translation are omitted.
p-STAT3,
p-STAT4,p-STAT5