Interleukin-17 signaling (Homo sapiens)

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14, 10, 16, 1914, 20, 21nucleoplasmcytosolcytosolIL17F IL17RA IL17RAIL17C IL17RA IL25 MAP kinaseactivation in TLRcascadeIL17RA:IL17RC:IL17Adimer,L17Fdimer,IL17A:IL17FIL17RAIL17C IL25dimer:IL17RA:IL17RBIL17A IL17RC IL17RAIL17RCIL17Cdimer:IL17RA:IL17REIL17C dimerIL17A dimer,L17Fdimer,IL17A:IL17FMAPK1/MAPK3signalingIL17F IL25 dimerIL17REIL17RE IL17RBIL17RA IL17RB IL25 IL17A 5-9, 11-13, 18...2, 3, 15, 17


Description

Interleukin-17 (IL17) is a family of cytokines (Kawaguchi et al. 2004, Gu et al. 2013). IL17A, the founding member of the family is able to induce the production of other cytokines and chemokines, such as IL6, IL8, and granulocyte colony-stimulating factor (G-CSF) in a variety of cell types, including activated T-cells. It plays a pivotal role in host defenses in response to microbial infection, and is involved in the pathogenesis of autoimmune diseases and allergic syndromes. IL17 activates several downstream signaling pathways including NFkB, MAPKs and C/EBPs, inducing the expression of antibacterial peptides, proinflammatory chemokines and cytokines and matrix metalloproteases (MMPs). IL17 can stabilize the mRNA of genes induced by TNF-alpha. IL17 signal transduction is mediated by the cytosolic adaptor molecule Act1 (also known as CIKS).

The receptor for IL17D is unknown (Gu et al. 2013). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 448424
Reactome-version 
Reactome version: 62
Reactome Author 
Reactome Author: Jupe, Steve

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Bibliography

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  2. Wang J, Whiteman MW, Lian H, Wang G, Singh A, Huang D, Denmark T.; ''A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1.''; PubMed Europe PMC Scholia
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  4. Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, Kolch W.; ''Raf family kinases: old dogs have learned new tricks.''; PubMed Europe PMC Scholia
  5. Al-Samadi A, Kouri VP, Salem A, Ainola M, Kaivosoja E, Barreto G, Konttinen YT, Hietanen J, Häyrinen-Immonen R.; ''IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer.''; PubMed Europe PMC Scholia
  6. Chang L, Karin M.; ''Mammalian MAP kinase signalling cascades.''; PubMed Europe PMC Scholia
  7. Gu C, Wu L, Li X.; ''IL-17 family: cytokines, receptors and signaling.''; PubMed Europe PMC Scholia
  8. Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J.; ''Cutting edge: interleukin 17 signals through a heteromeric receptor complex.''; PubMed Europe PMC Scholia
  9. Banerjee A, Gerondakis S.; ''Coordinating TLR-activated signaling pathways in cells of the immune system.''; PubMed Europe PMC Scholia
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  11. Bardwell AJ, Frankson E, Bardwell L.; ''Selectivity of docking sites in MAPK kinases.''; PubMed Europe PMC Scholia
  12. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  13. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  14. Kuriakose T, Rada B, Watford WT.; ''Tumor progression locus 2-dependent oxidative burst drives phosphorylation of extracellular signal-regulated kinase during TLR3 and 9 signaling.''; PubMed Europe PMC Scholia
  15. Raman M, Chen W, Cobb MH.; ''Differential regulation and properties of MAPKs.''; PubMed Europe PMC Scholia
  16. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  17. Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, Cohen JI, Spriggs MK.; ''Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor.''; PubMed Europe PMC Scholia
  18. Yoon S, Seger R.; ''The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions.''; PubMed Europe PMC Scholia
  19. Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J, Hackney J, Kim J, Zhou M, Lai J, Modrusan Z, Sai T, Lee W, Xu M, Caplazi P, Diehl L, de Voss J, Balazs M, Gonzalez L, Singh H, Ouyang W, Pappu R.; ''IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.''; PubMed Europe PMC Scholia
  20. You Z, Shi XB, DuRaine G, Haudenschild D, Tepper CG, Lo SH, Gandour-Edwards R, de Vere White RW, Reddi AH.; ''Interleukin-17 receptor-like gene is a novel antiapoptotic gene highly expressed in androgen-independent prostate cancer.''; PubMed Europe PMC Scholia
  21. Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD, Qian Y.; ''IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens.''; PubMed Europe PMC Scholia
  22. Awane M, Andres PG, Li DJ, Reinecker HC.; ''NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114987view16:51, 25 January 2021ReactomeTeamReactome version 75
113431view11:50, 2 November 2020ReactomeTeamReactome version 74
112633view16:01, 9 October 2020ReactomeTeamReactome version 73
101548view11:41, 1 November 2018ReactomeTeamreactome version 66
101083view21:24, 31 October 2018ReactomeTeamreactome version 65
100612view19:58, 31 October 2018ReactomeTeamreactome version 64
100163view16:43, 31 October 2018ReactomeTeamreactome version 63
99713view15:11, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93903view13:43, 16 August 2017ReactomeTeamreactome version 61
93476view11:24, 9 August 2017ReactomeTeamreactome version 61
86955view13:15, 15 July 2016MkutmonOntology Term : 'interleukin-17 family mediated signaling pathway' added !
86573view09:21, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
IL17A ProteinQ16552 (Uniprot-TrEMBL)
IL17A dimer,L17F dimer,IL17A:IL17FComplexR-HSA-447091 (Reactome) IL-17A and IL-17F are the best characterized members of the IL-17 cytokine family. Both are covalent homodimers, and also form IL-17A:IL-17F heterodimers.
IL17C dimer:IL17RA:IL17REComplexR-HSA-6787823 (Reactome)
IL17C ProteinQ9P0M4 (Uniprot-TrEMBL)
IL17C dimerComplexR-HSA-448410 (Reactome)
IL17F ProteinQ96PD4 (Uniprot-TrEMBL)
IL17RA ProteinQ96F46 (Uniprot-TrEMBL)
IL17RA:IL17RC:IL17A

dimer,L17F

dimer,IL17A:IL17F		ComplexR-HSA-448403 (Reactome)
IL17RAProteinQ96F46 (Uniprot-TrEMBL)
IL17RB ProteinQ9NRM6 (Uniprot-TrEMBL)
IL17RBProteinQ9NRM6 (Uniprot-TrEMBL)
IL17RC ProteinQ8NAC3 (Uniprot-TrEMBL)
IL17RCProteinQ8NAC3 (Uniprot-TrEMBL)
IL17RE ProteinQ8NFR9 (Uniprot-TrEMBL)
IL17REProteinQ8NFR9 (Uniprot-TrEMBL)
IL25 dimer:IL17RA:IL17RBComplexR-HSA-448378 (Reactome)
IL25 ProteinQ9H293 (Uniprot-TrEMBL)
IL25 dimerComplexR-HSA-448361 (Reactome)
MAP kinase

activation in TLR

cascade		PathwayR-HSA-450294 (Reactome) The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002).

There are three major groups of MAP kinases

  • the extracellular signal-regulated protein kinases ERK1/2,
  • the p38 MAP kinase
  • and the c-Jun NH-terminal kinases JNK.

ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).

MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.

The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.

The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear.

MAPK1/MAPK3 signalingPathwayR-HSA-5684996 (Reactome) The extracellular signal regulated kinases (ERKs) 1 and 2, also known as MAPK3 and MAPK1, are phosphorylated by the MAP2Ks 1 and 2 in response to a wide range of extracellular stimuli to promote differentiation, proliferation, cell motility, cell survivial, metabolism and transcription, among others (reviewed in Roskoski, 2012b; McKay and Morrison, 2007; Raman et al, 2007). In the classical pathway, MAPK1/3 activation is triggered by the GEF-mediated activation of RAS at the plasma membrane, leading to the activation of the RAF MAP3Ks (reviewed in McKay and Morrison, 2007; Matallanas et al, 2011; Wellbrock et al, 2004). However, many physiological and pathological stimuli have been found to activate MAPK1/3 independently of RAF and RAS, acting instead through MAP3Ks such as MOS, TPL2 and AMPK (Dawson et al, 2008; Wang et al, 2009; Kuriakose et al, 2014; Awane et al, 1999). Activated MAPK1/3 phosphorylate numerous targets in both the nucleus and cytoplasm (reviewed in Yoon and Seger, 2006; Roskoski 2012b).

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
IL17A dimer,L17F dimer,IL17A:IL17FR-HSA-447246 (Reactome)
IL17C dimer:IL17RA:IL17REArrowR-HSA-5678544 (Reactome)
IL17C dimerR-HSA-5678544 (Reactome)
IL17RA:IL17RC:IL17A

dimer,L17F

dimer,IL17A:IL17F		ArrowR-HSA-447246 (Reactome)
IL17RAR-HSA-447219 (Reactome)
IL17RAR-HSA-447246 (Reactome)
IL17RAR-HSA-5678544 (Reactome)
IL17RBR-HSA-447219 (Reactome)
IL17RCR-HSA-447246 (Reactome)
IL17RER-HSA-5678544 (Reactome)
IL25 dimer:IL17RA:IL17RBArrowR-HSA-447219 (Reactome)
IL25 dimerR-HSA-447219 (Reactome)
R-HSA-447219 (Reactome) Inferred from mouse:
Interleukin-25 (IL25, IL17E) dimers bind a receptor complex of Interleukin-17 receptor B (IL17RB) and Interleukin-17 receptor A (IL17RA) (Rickel et al. 2008). This is a Black Box event because the order of receptor binding is unclear.
R-HSA-447246 (Reactome) The Interleukin-17 receptor A/C complex is a dimer of Interleukin-17 receptor A (IL17RA) and Interleukin-17 receptor C (IL17RC). It binds interleukin-17A (IL17A) dimers, IL17F dimers and IL17A:IL17F heterodimers (IL17A:IL17F) (Yao et al. 1995, Toy et al. 2006).

IL17A and IL17F homodimers tend to disfavor binding of a second molecule of IL17RA to the receptor/ligand complex (Liu et al. 2013). Engagement of IL17RA or IL17RC by IL17A or IL17F brings about an allosteric 'preference' for the second receptor-binding site to engage a different receptor to form a heterodimeric receptor complex (Ely et al. 2003).

This is a Black Box event because the order of receptor binding is unclear.
R-HSA-5678544 (Reactome) The Interleukin-17C (IL17C) dimers bind a heterodimeric receptor complex of Interleukin-17 receptor A (IL17RA) and IL17RE, which is expressed predominantly on epithelial cells . IL17C has an essential role in host mucosal defense against infection. It is an epithelial cell derived cytokine regulated by Toll-like receptor (TLR) agonists to promote host-defense responses (Ramirez-Carrozzi et al. 2011). This is a Black Box event because the order of receptor binding is unclear.
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