Other interleukin signaling (Homo sapiens)

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16421142921353, 18, 3699272027195, 34141517926, 31cytosolSTXBP2 VAMP2 IL10RB FLT3LG dimerCSF3 IL10RB PTPRZ1SDC1STXA1:SNAP25,STXBP2,VAMP2CSF1 Caspase-3STX4CSF3R IL34 dimer:PTPRZ1CSF3RCASP3(176-277) IL34 IL34:CSF1:CSF1RTXLNA:STX3STX1ACD4:IL16(1212-1332)IL34 dimer:SDC1CD4SDC1 IFNL1 CSF1RRAF/MAP kinasecascadePTPRZ1 IL34 IL32CSF3 CD4 CSF1R SDC1 IL32:PRTN3TXLNAIFNLR1 IL34 IL34 IFNL1:IFNLR1:JAK1:IL10RB:TYK2FLT3LG PRTN3PRTN3 IFNLR1:JAK1STX3 JAK1 IL34 TXLNA:STX1ATYK2 IL16(1212-1332) IL34dimer:SDC1:CSF1RCSF3 dimer:CSF3RCSF3 CSF3 dimerCSF1R IL34TYK2 IL34:CSF1IL32 STX1A CSF1R:IL34 dimerFLT3LG dimer:2xFLT3CSF3R IL34 dimerCSF1IL16(1-1332)IL34 PI3K CascadeIL16(1212-1332)JAK1 FLT3LG IL16(1-1211)SNAP25 CASP3(29-175) TXLNA STX4 CSF1 FLT3 IL16(1212-1332)FLT3LG TXLNA:STX4FLT3LG dimer:FLT3STX1A FLT3CSF3 dimer:2xCSF3RIFNL1TXLNA CSF1R IFNLR1 IL34 TXLNA FLT3 IL10RB:TYK2STX313281, 2, 6-8, 10...1228


Interleukins are low molecular weight proteins that bind to cell surface receptors and act in an autocrine and/or paracrine fashion. They were first identified as factors produced by leukocytes but are now known to be produced by many other cells throughout the body. They have pleiotropic effects on cells which bind them, impacting processes such as tissue growth and repair, hematopoietic homeostasis, and multiple levels of the host defense against pathogens where they are an essential part of the immune system. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 449836
Reactome version: 66
Reactome Author 
Reactome Author: Jupe, Steve

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  1. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC
  2. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC
  3. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, Chen S, Brand N, Tarway M, Liu L, Sheikh F, Astemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O'Brien TR.; ''A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.''; PubMed Europe PMC
  4. Nandi S, Cioce M, Yeung YG, Nieves E, Tesfa L, Lin H, Hsu AW, Halenbeck R, Cheng HY, Gokhan S, Mehler MF, Stanley ER.; ''Receptor-type protein-tyrosine phosphatase ζ is a functional receptor for interleukin-34.''; PubMed Europe PMC
  5. Ryan TC, Cruikshank WW, Kornfeld H, Collins TL, Center DM.; ''The CD4-associated tyrosine kinase p56lck is required for lymphocyte chemoattractant factor-induced T lymphocyte migration.''; PubMed Europe PMC
  6. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC
  7. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC
  8. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC
  9. Nogami S, Satoh S, Nakano M, Shimizu H, Fukushima H, Maruyama A, Terano A, Shirataki H.; ''Taxilin; a novel syntaxin-binding protein that is involved in Ca2+-dependent exocytosis in neuroendocrine cells.''; PubMed Europe PMC
  10. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC
  11. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC
  12. Walter MR.; ''The molecular basis of IL-10 function: from receptor structure to the onset of signaling.''; PubMed Europe PMC
  13. Downward J.; ''PI 3-kinase, Akt and cell survival.''; PubMed Europe PMC
  14. Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT.; ''Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.''; PubMed Europe PMC
  15. Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN.; ''Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex.''; PubMed Europe PMC
  16. Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O'Mahony L, Palomares O, Rhyner C, Ouaked N, Schaffartzik A, Van De Veen W, Zeller S, Zimmermann M, Akdis CA.; ''Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases.''; PubMed Europe PMC
  17. Zhou P, Devadas K, Tewari D, Jegorow A, Notkins AL.; ''Processing, secretion, and anti-HIV-1 activity of IL-16 with or without a signal peptide in CD4+ T cells.''; PubMed Europe PMC
  18. Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM.; ''IL-28, IL-29 and their class II cytokine receptor IL-28R.''; PubMed Europe PMC
  19. Novick D, Rubinstein M, Azam T, Rabinkov A, Dinarello CA, Kim SH.; ''Proteinase 3 is an IL-32 binding protein.''; PubMed Europe PMC
  20. Zhang Y, Center DM, Wu DM, Cruikshank WW, Yuan J, Andrews DW, Kornfeld H.; ''Processing and activation of pro-interleukin-16 by caspase-3.''; PubMed Europe PMC
  21. Segaliny AI, Brion R, Mortier E, Maillasson M, Cherel M, Jacques Y, Le Goff B, Heymann D.; ''Syndecan-1 regulates the biological activities of interleukin-34.''; PubMed Europe PMC
  22. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC
  23. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC
  24. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC
  25. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC
  26. Hiraoka O, Anaguchi H, Ota Y.; ''Evidence for the ligand-induced conversion from a dimer to a tetramer of the granulocyte colony-stimulating factor receptor.''; PubMed Europe PMC
  27. Ségaliny AI, Brion R, Brulin B, Maillasson M, Charrier C, Téletchéa S, Heymann D.; ''IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization.''; PubMed Europe PMC
  28. Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMed Europe PMC
  29. Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF, Kastelein R, Hudak S, Wagner J, Mattson J.; ''Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs.''; PubMed Europe PMC
  30. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC
  31. Larsen A, Davis T, Curtis BM, Gimpel S, Sims JE, Cosman D, Park L, Sorensen E, March CJ, Smith CA.; ''Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains.''; PubMed Europe PMC
  32. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC
  33. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC
  34. Liu Y, Cruikshank WW, O'Loughlin T, O'Reilly P, Center DM, Kornfeld H.; ''Identification of a CD4 domain required for interleukin-16 binding and lymphocyte activation.''; PubMed Europe PMC
  35. Tamada T, Honjo E, Maeda Y, Okamoto T, Ishibashi M, Tokunaga M, Kuroki R.; ''Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex.''; PubMed Europe PMC
  36. Vandenbroeck K, Alvarez J, Swaminathan B, Alloza I, Matesanz F, Urcelay E, Comabella M, Alcina A, Fedetz M, Ortiz MA, Izquierdo G, Fernandez O, Rodriguez-Ezpeleta N, Matute C, Caillier S, Arroyo R, Montalban X, Oksenberg JR, Antigüedad A, Aransay A.; ''A cytokine gene screen uncovers SOCS1 as genetic risk factor for multiple sclerosis.''; PubMed Europe PMC


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101651view11:51, 1 November 2018ReactomeTeamreactome version 66
101187view21:39, 31 October 2018ReactomeTeamreactome version 65
100714view20:11, 31 October 2018ReactomeTeamreactome version 64
100264view16:57, 31 October 2018ReactomeTeamreactome version 63
99817view15:21, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93278view11:19, 9 August 2017ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
CASP3(176-277) ProteinP42574 (Uniprot-TrEMBL)
CASP3(29-175) ProteinP42574 (Uniprot-TrEMBL)
CD4 ProteinP01730 (Uniprot-TrEMBL)
CD4:IL16(1212-1332)ComplexR-HSA-449069 (Reactome)
CD4ProteinP01730 (Uniprot-TrEMBL)
CSF1 ProteinP09603 (Uniprot-TrEMBL)
CSF1ProteinP09603 (Uniprot-TrEMBL)
CSF1R ProteinP07333 (Uniprot-TrEMBL)
CSF1R:IL34 dimerComplexR-HSA-6787825 (Reactome)
CSF1RProteinP07333 (Uniprot-TrEMBL)
CSF3 ProteinP09919 (Uniprot-TrEMBL)
CSF3 dimer:2xCSF3RComplexR-HSA-8854746 (Reactome)
CSF3 dimer:CSF3RComplexR-HSA-6787729 (Reactome)
CSF3 dimerComplexR-HSA-8854719 (Reactome)
CSF3R ProteinQ99062 (Uniprot-TrEMBL)
CSF3RProteinQ99062 (Uniprot-TrEMBL)
Caspase-3ComplexR-HSA-350870 (Reactome)
FLT3 ProteinP36888 (Uniprot-TrEMBL)
FLT3LG ProteinP49771 (Uniprot-TrEMBL)
FLT3LG dimer:2xFLT3ComplexR-HSA-8854716 (Reactome)
FLT3LG dimer:FLT3ComplexR-HSA-6786754 (Reactome)
FLT3LG dimerComplexR-HSA-8854740 (Reactome)
FLT3ProteinP36888 (Uniprot-TrEMBL)
IFNL1 ProteinQ8IU54 (Uniprot-TrEMBL)
IFNL1:IFNLR1:JAK1:IL10RB:TYK2ComplexR-HSA-448637 (Reactome)
IFNL1ProteinQ8IU54 (Uniprot-TrEMBL)
IFNLR1 ProteinQ8IU57 (Uniprot-TrEMBL)
IFNLR1:JAK1ComplexR-HSA-8987216 (Reactome)
IL10RB ProteinQ08334 (Uniprot-TrEMBL)
IL10RB:TYK2ComplexR-HSA-6784360 (Reactome)
IL16(1-1211)ProteinQ14005 (Uniprot-TrEMBL)
IL16(1-1332)ProteinQ14005 (Uniprot-TrEMBL)
IL16(1212-1332) ProteinQ14005 (Uniprot-TrEMBL)
IL16(1212-1332)ProteinQ14005 (Uniprot-TrEMBL)
IL32 ProteinP24001 (Uniprot-TrEMBL)
IL32:PRTN3ComplexR-HSA-448647 (Reactome)
IL32ProteinP24001 (Uniprot-TrEMBL)
IL34 dimer:SDC1:CSF1RComplexR-HSA-9009560 (Reactome)
IL34 ProteinQ6ZMJ4 (Uniprot-TrEMBL)
IL34 dimer:PTPRZ1ComplexR-HSA-8981669 (Reactome)
IL34 dimer:SDC1ComplexR-HSA-9009553 (Reactome)
IL34 dimerComplexR-HSA-448628 (Reactome)
IL34:CSF1:CSF1RComplexR-HSA-9009491 (Reactome)
IL34:CSF1ComplexR-HSA-9009490 (Reactome)
IL34ProteinQ6ZMJ4 (Uniprot-TrEMBL)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
PI3K CascadePathwayR-HSA-109704 (Reactome) The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival.
PRTN3 ProteinP24158 (Uniprot-TrEMBL)
PRTN3ProteinP24158 (Uniprot-TrEMBL)
PTPRZ1 ProteinP23471 (Uniprot-TrEMBL)
PTPRZ1ProteinP23471 (Uniprot-TrEMBL)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
SDC1 ProteinP18827 (Uniprot-TrEMBL)
SDC1ProteinP18827 (Uniprot-TrEMBL)
SNAP25 ProteinP60880 (Uniprot-TrEMBL)
STX1A ProteinQ16623 (Uniprot-TrEMBL)
STX1AProteinQ16623 (Uniprot-TrEMBL)
STX3 ProteinQ13277 (Uniprot-TrEMBL)
STX3ProteinQ13277 (Uniprot-TrEMBL)
STX4 ProteinQ12846 (Uniprot-TrEMBL)
STX4ProteinQ12846 (Uniprot-TrEMBL)
STXA1:SNAP25,STXBP2, VAMP2ComplexR-HSA-9014068 (Reactome)
STXBP2 ProteinQ15833 (Uniprot-TrEMBL)
TXLNA ProteinP40222 (Uniprot-TrEMBL)
TXLNA:STX1AComplexR-HSA-449116 (Reactome)
TXLNA:STX3ComplexR-HSA-9014059 (Reactome)
TXLNA:STX4ComplexR-HSA-9014081 (Reactome)
TXLNAProteinP40222 (Uniprot-TrEMBL)
TYK2 ProteinP29597 (Uniprot-TrEMBL)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
CD4:IL16(1212-1332)ArrowR-HSA-449087 (Reactome)
CD4R-HSA-449087 (Reactome)
CSF1R-HSA-9009488 (Reactome)
CSF1R:IL34 dimerArrowR-HSA-6787820 (Reactome)
CSF1RR-HSA-6787820 (Reactome)
CSF1RR-HSA-9009485 (Reactome)
CSF1RR-HSA-9009554 (Reactome)
CSF3 dimer:2xCSF3RArrowR-HSA-8854738 (Reactome)
CSF3 dimer:CSF3RArrowR-HSA-6787737 (Reactome)
CSF3 dimer:CSF3RR-HSA-8854738 (Reactome)
CSF3 dimerR-HSA-6787737 (Reactome)
CSF3RR-HSA-6787737 (Reactome)
CSF3RR-HSA-8854738 (Reactome)
Caspase-3mim-catalysisR-HSA-449073 (Reactome)
FLT3LG dimer:2xFLT3ArrowR-HSA-8854736 (Reactome)
FLT3LG dimer:FLT3ArrowR-HSA-6786789 (Reactome)
FLT3LG dimer:FLT3R-HSA-8854736 (Reactome)
FLT3LG dimerR-HSA-6786789 (Reactome)
FLT3R-HSA-6786789 (Reactome)
FLT3R-HSA-8854736 (Reactome)
IFNL1:IFNLR1:JAK1:IL10RB:TYK2ArrowR-HSA-448661 (Reactome)
IFNL1R-HSA-448661 (Reactome)
IFNLR1:JAK1R-HSA-448661 (Reactome)
IL10RB:TYK2R-HSA-448661 (Reactome)
IL16(1-1211)ArrowR-HSA-449073 (Reactome)
IL16(1-1332)R-HSA-449073 (Reactome)
IL16(1212-1332)ArrowR-HSA-449073 (Reactome)
IL16(1212-1332)ArrowR-HSA-449077 (Reactome)
IL16(1212-1332)R-HSA-449077 (Reactome)
IL16(1212-1332)R-HSA-449087 (Reactome)
IL32:PRTN3ArrowR-HSA-448591 (Reactome)
IL32R-HSA-448591 (Reactome)
IL34 dimer:SDC1:CSF1RArrowR-HSA-9009554 (Reactome)
IL34 dimer:PTPRZ1ArrowR-HSA-8981657 (Reactome)
IL34 dimer:SDC1ArrowR-HSA-9009558 (Reactome)
IL34 dimer:SDC1R-HSA-9009554 (Reactome)
IL34 dimerArrowR-HSA-448632 (Reactome)
IL34 dimerR-HSA-6787820 (Reactome)
IL34 dimerR-HSA-8981657 (Reactome)
IL34 dimerR-HSA-9009558 (Reactome)
IL34:CSF1:CSF1RArrowR-HSA-9009485 (Reactome)
IL34:CSF1ArrowR-HSA-9009488 (Reactome)
IL34:CSF1R-HSA-9009485 (Reactome)
IL34R-HSA-448632 (Reactome)
IL34R-HSA-9009488 (Reactome)
PRTN3R-HSA-448591 (Reactome)
PTPRZ1R-HSA-8981657 (Reactome)
R-HSA-448591 (Reactome) IL-32 has properties of a typical pro-inflammatory mediator, stimulating TNF-alpha, IL-1beta and IL-8 production, and activating the NF-kappaB and p38 mitogen-activated protein (MAP) kinase pathways. It is produced mainly by T, natural killer, epithelial and monocyte cells after stimulation by Interleukin-2, Interleukin-18 or IFN-gamma (Kim et al. 2005). IL-32 can bind proteinase 3, a neutrophil-derived serine protease, but its (assumed) receptor is unknown.
R-HSA-448632 (Reactome) interleukin-34 (IL34) was identified as a potent activator of monocytes and macrophages, signaling through Colony-stimulating factor-1 (CSF1) receptor (CSF1R) with a distinct tissue distribution from CSF1 (Lin et al. 2008). IL34 and CSF1 share many functional properties. IL34 has no appreciable sequence similarity with any other protein but shares a four-helix bundle structure seen in CSF1 (Garceau et al. 2010, Liu et al. 2012). IL34 forms a noncovalently linked dimer (Ma et al. 2012) whereas CSF1 contains an intersubunit disulfide bond. The structure of the IL34:CSF1R complex shows a similar ligand-receptor assembly to that of CSF1:CSF1R.
R-HSA-448661 (Reactome) 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).
R-HSA-449073 (Reactome) The mature and biologically active secreted interleukin-16 (IL16) is a 13-kDa carboxy terminal peptide derived from a larger intracellular precursor protein. Cleavage of IL16 from the propeptide is mediated by caspase-3. IL16 is a chemoattractant for a variety of cell types that express the cell surface antigen CD4.
R-HSA-449077 (Reactome) Interleukin-16 (IL16) does not contain a consensus secretory leader sequence, and the mechanism for its release has not been elucidated. Amino-terminal deletions of IL16 reduce its capacity for secretion (Zhou et al. 1999), but the significance of this is unclear.
R-HSA-449087 (Reactome) CD4 is a receptor for Interleukin-16 (IL16), explaining how IL16 acts as a chemoattractant for a variety of CD4+ immune cells (Cruikshank et al. 2000, Cruikshank & Little 2008). Signaling mediated by CD4 requires the amino acid sequence W345 to S350, located in the proximal end of the D4 domain. CD4 does not appear to require a co-receptor for IL16. Data from CD4 knockout mice suggests that there may be an additional IL16 receptor (Mathy et al. 2000).
R-HSA-449117 (Reactome) Interleukin-14, renamed alpha-taxilin (TXLNA) was originally described as High molecular weight B-cell growth factor (Ambrus et al. 1994). TXLNA binds several forms of syntaxin (Nogami et al. 2003), but not when they are complexed with SNAP25, VAMP2 or STXBP1, suggesting that TXLNA interacts with syntaxins outside the SNARE complex. This observation and a predicted role in intracellular vesicle trafficking led to renaming of the gene. Txlna transgenic mice show a phenotype similar to systemic lupus erythematosus and Sjogren's syndrome (Shen et al. 2006).
R-HSA-6786789 (Reactome) FLT3 is a member of the Class III Receptor Tyrosine Kinase Family, which also includes FMS, KIT, PDGFRA and PDGFRB. It binds the cytokine FLT3LG (Hannum et al. 1994), which regulates differentiation, proliferation and survival of hematopoietic progenitor cells and dendritic cells.

FLT3LG is probably dimeric. Binding to monomeric FLT3 induces receptor dimerization (Verstraete et al. 2011, Grafone et al. 2012), which promotes phosphorylation of the tyrosine kinase domain, activating the receptor and consequently the downstream effectors. Early studies of FLT3 using a chimeric receptor composed of the extracellular domain of human FMS and the transmembrane and cytoplasmic domains of FLT3 demonstrated the activation of PLCG1, RASA1, SHC, GRB2, VAV, FYN, and SRC pathways. PLCG1, SHC, GRB2, and FYN were found to directly associate with the cytoplasmic domain of FLT3 (Dosil et al. 1993). Later studes using the full-length human receptor identified that FLT3LG binding to FLT3 leads to FLT3 autophosphorylation, association of FLT3 with GRB2, tyrosine phosphorylation of SHC and CBL, formation of a complex that includes CBL, the p85 subunit of PI3K and GAB2, and tyrosine phosphorylation of GAB1 and GAB2 and their association with PTPN11 (SHP-2) and GRB2. PTPN11 (SHP-2), but not PTPN6 (SHP-1) binds GRB2 directly and becomes tyrosine-phosphorylated in response to FLT3LG stimulation. INPP5D (SHIP) also becomes tyrosine-phosphorylated after FLT3LG stimulation but binds to SHC. GAB1 and GAB2 are rapidly tyrosine phosphorylated after FLT3LG stimulation of cells, interacting with tyrosine-phosphorylated PTPN11, p85 subunit of PI3K, GRB2, and SHC (Zhang & Broxmeyer 2000). GAB may mediate the downstream activation of PTPN11, PI3K and thereby PDK1 and AKt which activate the mTOR pathway (Grafone et al. 2012), and possibly the Ras/Raf/MAPK pathway. (Zhang et al. 1999, Marchetto et al. 1999, Zhang e& Broxmeyer 2000). Activation of FLT3 leads to limited activation of STAT5A via a JAK-independent mechanism (Zhang et al. 2000).

FLT3 is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Both types of mutation constitutively activate FLT3 (Small 2006).
R-HSA-6787737 (Reactome) The granulocyte colony-stimulating factor receptor (CSF3R, GCSFR, CD114) is a cell-surface receptor for the granulocyte colony-stimulating factor (CSF3, GCSF) (Larsen et al. 1990, Panapoulos & Watowich 2008). It is present on precursor cells in the bone marrow. CSF3 initiates cell proliferation and differentiation into mature neutrophilic granulocytes and macrophages. CSF3 exists as a dimer and higher order oligomeric structures; only the dimer exhibits high affinity binding (Hiraoka & Anaguchi et al. 1994). CSF3R ligand-binding is associated with dimerization of the receptor (Aritomi et al. 1999, Tamada et al. 2006, Layton & Hall 2006) and signal transduction through Jak/STAT, Lyn and Erk1/2. Mutations in CSF3R are a cause of Kostmann syndrome, also known as severe congenital neutropenia (Zeidler & Welte 2002, Vandenberghe & Beel 2011).
R-HSA-6787820 (Reactome) The receptor for Interleukin-34 (IL34) is colony stimulating factor 1 receptor (CSF1R), also called macrophage colony stimulating factor receptor (M-CSF-R). Dimeric IL34 and CSF1 bind the same general region of CSF1R, interacting with overlapping but distinct epitopes. Ligand binding leads to receptor dimerisation (Ma et al. 2012, Liu et al. 2012). Like CSF1, IL34 stimulation of CSF1R leads to phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2 in human monocytes (Lin et al. 2008). CSF1R activates several signaling pathways including JAK-STAT3, 5A/B, phosphorylation of PIK3R1, PLCG2, GRB2, SLA2 and CBL. PLCG2 phosphorylation leads to increassed production of the cellular signaling molecules diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3), which activate protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3 kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of MAPK1 (ERK2) or MAPK3 (ERK1) and the SRC family kinases SRC, FYN and YES1. Activated CSF1R binds GRB2 and promotes tyrosine phosphorylation of SHC1 and INPP5D (SHIP1). Signaling is down regulated by protein phosphatases such as INPP5D that can dephosphorylate the receptor and its downstream effectors.
R-HSA-8854736 (Reactome) Binding of FLT3LG to monomeric FLT3 induces receptor dimerization (Verstraete et al. 2011, Grafone et al. 2012).
R-HSA-8854738 (Reactome) CSF3R ligand-binding is associated with dimerization of the receptor (Aritomi et al. 1999, Tamada et al. 2006, Layton & Hall 2006) and signal transduction through Jak/STAT, Lyn and Erk1/2.
R-HSA-8981657 (Reactome) Interleukin-34 (IL34) signals via the Colony-stimulating factor-1 receptor (CSF1R). It can also bind Receptor-type protein-tyrosine phosphatase zeta (PTPRZ1), a cell surface chondroitin sulfate (CS) proteoglycan. PTPRZ1 is primarily expressed on neural progenitor and glial cells. IL34 selectively bound PTPRZ1 in CSF1R-deficient U251 human glioblastoma cell lysates, inhibiting proliferation, clonogenicity and motility, and promoting an increase in tyrosine phosphorylation of focal adhesion kinase 1 (PTK2) and paxillin (PXN) (Nandii et al. 2013).
R-HSA-9009485 (Reactome) Interleukin-34 (IL34) can bind Macrophage colony-stimulating factor 1 (CSF1). The IL34:CSF1 heteromer may bind Macrophage colony-stimulating factor 1 receptor (CSF1R) facilitating receptor maturation and cellular trafficking. Consequently, downstream signaling pathways are activated (Segaliny et al. 2015). Ultimately, these events lead to the release of pro-inflammatory chemokines regulating the innate immunity and inflammation. The exact binding mechanism of IL34:CSF1 to CSF1R is unclear. Hence, this interaction is represented as a black box event.
R-HSA-9009488 (Reactome) Interleukin-34 (IL34) can bind Macrophage colony-stimulating factor 1 (CSF1) to form a heteromer, which subsequently binds CSF1R (Segaliny et al. 2015).
R-HSA-9009554 (Reactome) Interleukin-34 (IL34) can bind Syndecan-1 (SDC1), a cell surface proteoglycan. Low levels of SDC1 may sequester IL34 at the cell surface and prevent it from binding Macrophage colony-stimulating factor 1 receptor (CSF1R), while high SDC1 levels may facilitate IL34-CSF1R signaling (Segaliny et al. 2015). Ultimately, these events lead to the release of pro-inflammatory chemokines regulating the innate immunity and inflammation. The precise interaction between IL34:SDC1 and CSF1R is unknown. Hence, this interaction is represented as an uncertain black box event.
R-HSA-9009558 (Reactome) Interleukin-34 (IL34) is involved in the survival, proliferation and differentiation of monocytes and macrophages. Syndecan-1 (SDC1) is a cell surface proteoglycan that contains the chondroitin sulphate and primarily functions to link the cytoskeleton to the interstitial matrix. IL34 dimers can bind to the chondroitin sulphate of SDC1. Subsequently, SDC1 modulates IL34-induced CSF1R signaling pathways (Segaliny et al. 2015). Ultimately, these events lead to the release of pro-inflammatory chemokines regulating the innate immunity and inflammation.
R-HSA-9014052 (Reactome) Interleukin-14, renamed alpha-taxilin (TXLNA) was originally described as High molecular weight B-cell growth factor (Ambrus et al. 1994). TXLNA binds several forms of syntaxin (Nogami et al. 2003), but not when they are complexed with SNAP25, VAMP2 or STXBP1, suggesting that TXLNA interacts with syntaxins outside the SNARE complex. This observation and a predicted role in intracellular vesicle trafficking led to renaming of the gene. Txlna transgenic mice show a phenotype similar to systemic lupus erythematosus and Sjogren's syndrome (Shen et al. 2006).
R-HSA-9014074 (Reactome) Interleukin-14, renamed alpha-taxilin (TXLNA) was originally described as High molecular weight B-cell growth factor (Ambrus et al. 1994). TXLNA binds several forms of syntaxin (Nogami et al. 2003), but not when they are complexed with SNAP25, VAMP2 or STXBP1, suggesting that TXLNA interacts with syntaxins outside the SNARE complex. This observation and a predicted role in intracellular vesicle trafficking led to renaming of the gene. Txlna transgenic mice show a phenotype similar to systemic lupus erythematosus and Sjogren's syndrome (Shen et al. 2006).
SDC1R-HSA-9009558 (Reactome)
STX1AR-HSA-449117 (Reactome)
STX3R-HSA-9014052 (Reactome)
STX4R-HSA-9014074 (Reactome)
STXA1:SNAP25,STXBP2, VAMP2TBarR-HSA-449117 (Reactome)
TXLNA:STX1AArrowR-HSA-449117 (Reactome)
TXLNA:STX3ArrowR-HSA-9014052 (Reactome)
TXLNA:STX4ArrowR-HSA-9014074 (Reactome)
TXLNAR-HSA-449117 (Reactome)
TXLNAR-HSA-9014052 (Reactome)
TXLNAR-HSA-9014074 (Reactome)
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