Interleukin-17 signaling (Homo sapiens)

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Bibliography

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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
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16. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
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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
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History

External references

DataNodes

Name	Type	Database reference	Comment
IL17A	Protein	Q16552 (Uniprot-TrEMBL)
IL17A dimer,L17F dimer,IL17A:IL17F	Complex	R-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:IL17RE	Complex	R-HSA-6787823 (Reactome)
IL17C	Protein	Q9P0M4 (Uniprot-TrEMBL)
IL17C dimer	Complex	R-HSA-448410 (Reactome)
IL17F	Protein	Q96PD4 (Uniprot-TrEMBL)
IL17RA	Protein	Q96F46 (Uniprot-TrEMBL)
IL17RA:IL17RC:IL17A dimer,L17F dimer,IL17A:IL17F	Complex	R-HSA-448403 (Reactome)
IL17RA	Protein	Q96F46 (Uniprot-TrEMBL)
IL17RB	Protein	Q9NRM6 (Uniprot-TrEMBL)
IL17RB	Protein	Q9NRM6 (Uniprot-TrEMBL)
IL17RC	Protein	Q8NAC3 (Uniprot-TrEMBL)
IL17RC	Protein	Q8NAC3 (Uniprot-TrEMBL)
IL17RE	Protein	Q8NFR9 (Uniprot-TrEMBL)
IL17RE	Protein	Q8NFR9 (Uniprot-TrEMBL)
IL25 dimer:IL17RA:IL17RB	Complex	R-HSA-448378 (Reactome)
IL25	Protein	Q9H293 (Uniprot-TrEMBL)
IL25 dimer	Complex	R-HSA-448361 (Reactome)
MAP kinase activation	Pathway	R-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 signaling	Pathway	R-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

Source	Target	Type	Database reference	Comment
IL17A dimer,L17F dimer,IL17A:IL17F			R-HSA-447246 (Reactome)
	IL17C dimer:IL17RA:IL17RE	Arrow	R-HSA-5678544 (Reactome)
IL17C dimer			R-HSA-5678544 (Reactome)
	IL17RA:IL17RC:IL17A dimer,L17F dimer,IL17A:IL17F	Arrow	R-HSA-447246 (Reactome)
IL17RA			R-HSA-447219 (Reactome)
IL17RA			R-HSA-447246 (Reactome)
IL17RA			R-HSA-5678544 (Reactome)
IL17RB			R-HSA-447219 (Reactome)
IL17RC			R-HSA-447246 (Reactome)
IL17RE			R-HSA-5678544 (Reactome)
	IL25 dimer:IL17RA:IL17RB	Arrow	R-HSA-447219 (Reactome)
IL25 dimer			R-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.