Interleukin-9 signaling (Homo sapiens)

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3, 15, 176, 191, 7, 98, 9, 12, 161818183, 9, 122-4, 101616, 185, 10, 11, 1616, 18cytosolnucleoplasmADPIL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3STAT1 JAK1 STAT5A STAT3 JAK1 IL2RG p-Y705-STAT3 STAT3 IL9R ATPIL9 STAT5B JAK1 p-Y701-STAT1:p-Y705-STAT3IL9 IL2RG p-Y649-STAT5A IL9:IL9R:JAK1:IL2RG:p-Y904,939-JAK3p-Y904,939-JAK3 p-Y701-STAT1 p-Y649-STAT5A, p-STAT5B p-Y904,939-JAK3 ADPIL9RJAK1p-Y701-STAT1 IL9R p-Y701-STAT1:p-Y705-STAT3STAT5B JAK3p-Y701-STAT1,p-Y705-STAT3,p-Y649-STAT5A,p-STAT5BJAK3 IL9 p-Y116-IL9R IL9:IL9R:JAK1:IL2RG:JAK3IL2RG IL9 IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:STAT1,STAT3,STAT5A,STAT5Bp-STAT5A,p-STAT5Bdimerp-Y649-STAT5A, p-STAT5B p-Y116-IL9R p-Y701-STAT1 p-Y701-STAT1 IL9R:JAK1IL2RG JAK1 JAK1 p-Y705-STAT3JAK1 p-Y649-STAT5A,p-STAT5Bp-Y-STAT1 dimerp-Y705-STAT3 IL9 JAK3 IL2RG p-Y705-STAT3 IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:p-Y701-STAT1,p-Y705-STAT3,p-Y649-STAT5p-Y904,939-JAK3 p-Y904,939-JAK3 p-Y701-STAT1ADPSTAT5A IL2RGSTAT1 ATPp-Y701-STAT1 p-STAT5B STAT1,STAT3,STAT5A,STAT5Bp-Y649-STAT5A ATPp-STAT5B IL9R IL9p-Y705-STAT3 IL2RG IL2RG:JAK3p-Y116-IL9R 51416135, 1655, 165161616145


Interleukin 9 (IL9) binds interleukin 9 receptor a chain (IL9R) and the interleukin 2 receptor common gamma chain (IL2RG) to initiate IL9 signaling downstream cascade. IL9R colocalize with Interleukin 2 receptor α chain and MHC molecules in lipid rafts of human T lymphoma cells (Nizsalóczki et al. 2014). IL2RG is essential for IL9 dependent growth signal transduction (Kimura et al. 1995). IL9R (glycoprotein of 64 kDa) has saturable and specific binding sites with a Kd of 100 pM (Renauld et al. 1992). The activated IL9R complex recruits tyrosine kinase proteins from the Janus kinase (JAK) family: JAK1 (JAK1) and JAK3 (JAK3) for subsequent activation of the Signal transducer and activator of transcription (STAT) factors STAT1, STAT3 and STAT5. The activated STATs form STAT5 dimers and STAT1:STAT3 heterodimers (Neurath & Finotto 2016, Li & Rostami 2010). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 8985947
Reactome version: 66
Reactome Author 
Reactome Author: Jupe, Steve

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  1. Longphre M, Li D, Gallup M, Drori E, Ordoñez CL, Redman T, Wenzel S, Bice DE, Fahy JV, Basbaum C.; ''Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells.''; PubMed Europe PMC
  2. Renauld JC, Druez C, Kermouni A, Houssiau F, Uyttenhove C, Van Roost E, Van Snick J.; ''Expression cloning of the murine and human interleukin 9 receptor cDNAs.''; PubMed Europe PMC
  3. Nizsalóczki E, Csomós I, Nagy P, Fazekas Z, Goldman CK, Waldmann TA, Damjanovich S, Vámosi G, Mátyus L, Bodnár A.; ''Distinct spatial relationship of the interleukin-9 receptor with interleukin-2 receptor and major histocompatibility complex glycoproteins in human T lymphoma cells.''; PubMed Europe PMC
  4. Kimura Y, Takeshita T, Kondo M, Ishii N, Nakamura M, Van Snick J, Sugamura K.; ''Sharing of the IL-2 receptor gamma chain with the functional IL-9 receptor complex.''; PubMed Europe PMC
  5. Cheng H, Ross JA, Frost JA, Kirken RA.; ''Phosphorylation of human Jak3 at tyrosines 904 and 939 positively regulates its activity.''; PubMed Europe PMC
  6. Nelson BH, Lord JD, Greenberg PD.; ''Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation.''; PubMed Europe PMC
  7. Kang LY, Yang YC.; ''Activation of junB and c-myc primary response genes by interleukin 9 in a human factor-dependent cell line.''; PubMed Europe PMC
  8. Demoulin JB, Uyttenhove C, Lejeune D, Mui A, Groner B, Renauld JC.; ''STAT5 activation is required for interleukin-9-dependent growth and transformation of lymphoid cells.''; PubMed Europe PMC
  9. Yamasaki A, Saleh A, Koussih L, Muro S, Halayko AJ, Gounni AS.; ''IL-9 induces CCL11 expression via STAT3 signalling in human airway smooth muscle cells.''; PubMed Europe PMC
  10. Haan C, Rolvering C, Raulf F, Kapp M, Drückes P, Thoma G, Behrmann I, Zerwes HG.; ''Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors.''; PubMed Europe PMC
  11. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ.; ''Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2.''; PubMed Europe PMC
  12. Demoulin JB, Van Snick J, Renauld JC.; ''Interleukin-9 (IL-9) induces cell growth arrest associated with sustained signal transducer and activator of transcription activation in lymphoma cells overexpressing the IL-9 receptor.''; PubMed Europe PMC
  13. Hofmann SR, Lam AQ, Frank S, Zhou YJ, Ramos HL, Kanno Y, Agnello D, Youle RJ, O'Shea JJ.; ''Jak3-independent trafficking of the common gamma chain receptor subunit: chaperone function of Jaks revisited.''; PubMed Europe PMC
  14. Wu L, Zepp JA, Qian W, Martin BN, Ouyang W, Yin W, Bunting KD, Aronica M, Erzurum S, Li X.; ''A novel IL-25 signaling pathway through STAT5.''; PubMed Europe PMC
  15. Neurath MF, Finotto S.; ''IL-9 signaling as key driver of chronic inflammation in mucosal immunity.''; PubMed Europe PMC
  16. Demoulin JB, Uyttenhove C, Van Roost E, DeLestré B, Donckers D, Van Snick J, Renauld JC.; ''A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9.''; PubMed Europe PMC
  17. Li H, Rostami A.; ''IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity.''; PubMed Europe PMC
  18. Bauer JH, Liu KD, You Y, Lai SY, Goldsmith MA.; ''Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis.''; PubMed Europe PMC
  19. Zhu MH, Berry JA, Russell SM, Leonard WJ.; ''Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3 to Il-2Rbeta.''; PubMed Europe PMC


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101569view11:43, 1 November 2018ReactomeTeamreactome version 66
101105view21:27, 31 October 2018ReactomeTeamreactome version 65
100634view20:01, 31 October 2018ReactomeTeamreactome version 64
100184view16:46, 31 October 2018ReactomeTeamreactome version 63
99734view15:12, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99378view13:25, 31 October 2018DeSlOntology Term : 'interleukin-9 signaling pathway' added !
99367view12:48, 31 October 2018ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
IL2RG ProteinP31785 (Uniprot-TrEMBL)
IL2RG:JAK3ComplexR-HSA-451911 (Reactome)
IL2RGProteinP31785 (Uniprot-TrEMBL)
IL9 ProteinP15248 (Uniprot-TrEMBL)
IL9:IL9R:JAK1:IL2RG:JAK3ComplexR-HSA-449785 (Reactome)
IL9:IL9R:JAK1:IL2RG:p-Y904,939-JAK3ComplexR-HSA-8985938 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:STAT1,STAT3,STAT5A,STAT5BComplexR-HSA-8985893 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:p-Y701-STAT1,p-Y705-STAT3,p-Y649-STAT5ComplexR-HSA-8985982 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3ComplexR-HSA-8985997 (Reactome)
IL9ProteinP15248 (Uniprot-TrEMBL)
IL9R ProteinQ01113 (Uniprot-TrEMBL)
IL9R:JAK1ComplexR-HSA-8985962 (Reactome) JAK1 was constitutively associated with the Interleukin-9 receptor (IL9RA) (Demulin et al. 1996).
IL9RProteinQ01113 (Uniprot-TrEMBL)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
JAK1ProteinP23458 (Uniprot-TrEMBL)
JAK3 ProteinP52333 (Uniprot-TrEMBL)
JAK3ProteinP52333 (Uniprot-TrEMBL)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT1,STAT3,STAT5A,STAT5BComplexR-HSA-9005640 (Reactome)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
p-STAT5A,p-STAT5B dimerComplexR-HSA-8985941 (Reactome)
p-STAT5B ProteinP51692 (Uniprot-TrEMBL)
p-Y-STAT1 dimerComplexR-HSA-8985970 (Reactome)
p-Y116-IL9R ProteinQ01113 (Uniprot-TrEMBL)
p-Y649-STAT5A ProteinP42229 (Uniprot-TrEMBL) Inferred from mouse: Interleukin-25 (IL25 or IL17E) stimulation had any effect on the phosphorylation of STAT proteins. Although IL25 had no effect on the activation of Signal transducer and activator of transcription 6 (STAT6) and Signal transducer and activator of transcription 3 (STAT3), IL25 stimulation led to the activation of Signal transducer and activator of transcription 5A or 5B (STAT5), as indicated by the phosphorylation of STAT5 (Wu et al. 2015).
This is a black box event since the details about of the phosphorylated region could be incomplete.
p-Y649-STAT5A, p-STAT5BComplexR-HSA-8983121 (Reactome)
p-Y649-STAT5A, p-STAT5B R-HSA-8983121 (Reactome)
p-Y701-STAT1 ProteinP42224 (Uniprot-TrEMBL)
p-Y701-STAT1,p-Y705-STAT3,p-Y649-STAT5A,p-STAT5BComplexR-HSA-9010175 (Reactome)
p-Y701-STAT1:p-Y705-STAT3ComplexR-HSA-8985942 (Reactome)
p-Y701-STAT1:p-Y705-STAT3ComplexR-HSA-8985949 (Reactome)
p-Y701-STAT1ProteinP42224 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-Y705-STAT3ProteinP40763 (Uniprot-TrEMBL)
p-Y904,939-JAK3 ProteinP52333 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-8985914 (Reactome)
ADPArrowR-HSA-8985973 (Reactome)
ADPArrowR-HSA-8985988 (Reactome)
ATPR-HSA-8985914 (Reactome)
ATPR-HSA-8985973 (Reactome)
ATPR-HSA-8985988 (Reactome)
IL2RG:JAK3ArrowR-HSA-451895 (Reactome)
IL2RG:JAK3R-HSA-8963734 (Reactome)
IL2RGR-HSA-451895 (Reactome)
IL9:IL9R:JAK1:IL2RG:JAK3ArrowR-HSA-8963734 (Reactome)
IL9:IL9R:JAK1:IL2RG:JAK3R-HSA-8985914 (Reactome)
IL9:IL9R:JAK1:IL2RG:p-Y904,939-JAK3ArrowR-HSA-8985914 (Reactome)
IL9:IL9R:JAK1:IL2RG:p-Y904,939-JAK3R-HSA-8985973 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:STAT1,STAT3,STAT5A,STAT5BArrowR-HSA-8985929 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:STAT1,STAT3,STAT5A,STAT5BR-HSA-8985988 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:p-Y701-STAT1,p-Y705-STAT3,p-Y649-STAT5ArrowR-HSA-8985988 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:p-Y701-STAT1,p-Y705-STAT3,p-Y649-STAT5R-HSA-8985900 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3ArrowR-HSA-8985900 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3ArrowR-HSA-8985973 (Reactome)
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3R-HSA-8985929 (Reactome)
IL9R-HSA-8963734 (Reactome)
IL9R:JAK1ArrowR-HSA-9011748 (Reactome)
IL9R:JAK1R-HSA-8963734 (Reactome)
IL9RR-HSA-9011748 (Reactome)
JAK1R-HSA-9011748 (Reactome)
JAK3R-HSA-451895 (Reactome)
R-HSA-451895 (Reactome) Cytokine receptor common gamma subunit (IL2RG, IL-2 receptor gamma chain, Gc) associates with Tyrosine-protein kinase JAK3 (JAK3). The carboxyl-terminal region of IL2RG is important for this association (Miyazaki et al. 1994, Zhu et al. 1998, Russel et al. 2004, Chen et al.1997, Nelson et al.1994) as well as the FERM domain in JAK3 (Zhou et al. 2001).
R-HSA-8963734 (Reactome) Interleukin-9 (IL9) binds to the Interleukin-9 receptor (IL9R) and Cytokine common gamma chain subunit (IL2RG) forming a ligand-receptor complex (Kimura et al 1995, Nizsalóczki et al. 2014). IL2RG is essential for IL9 dependent growth signal transduction (Kimura et al. 1995). IL9R (glycoprotein of 64 kDa) has saturable and specific binding sites with a Kd of 100 pM (Renauld et al. 1992). IL9R colocalize with Interleukin-2 receptors and MHC molecules in lipid rafts of human T lymphoma cells so it is suggested that interactions within these membrane clusters could affect the assembly and signaling capability of the receptors (Nizsalóczki et al. 2014). Moreover, there is evidence that Tyrosine protein kinase JAK1 (JAK1) cooperates with Tyrosine protein kinase JAK3 (JAK3) in signaling through IL2RG-containing receptors (Haan et al. 2011).
R-HSA-8985900 (Reactome) Signal transducer and activator of transcription 1-alpha/beta (STAT1), STAT3 and STAT5A/STAT5B (collectively termed STAT5) are believed to dissociate from the Interleukin 9:Interleukin 9 receptor complex.

STAT1 (Demoulin et al, 1996), STAT3 (Yamasaki et al. 2010) and STAT5 (Demoulin et al. 2000) have been identified as part of complexes associated with DNA in the nucleus following IL9 stimulation. All 3 STATs are believed to follow the standard model for STAT signaling, namely dissociation from the receptor complex, dimerization and translocation to the nucleus (Demoulin et al. 2000, Demoulin et al. 2000, Levy & Darnell 2002).
R-HSA-8985914 (Reactome) Tyrosine-protein kinase JAK3 (JAK3) is believed to become phosphorylated after IL9:IL9R interaction as this is thought to be a mechanism common to all receptors that incorporate IL2RG (Haan et al. 2011). There is no clear evidence for JAK1 phosphorylation by IL9 treatment, except in pathological states (Hornakova et al. 2009, Gordon et al. 2010).

This is a black box event because phosphorylation of JAK3 is inferred from the signaling mechanism of the related IL2 receptor (Johnston et al. 1994).
R-HSA-8985929 (Reactome) Signal transducer and activator of transcription 1-alpha/beta (STAT1), STAT3, STAT5A and STAT5B bind to the Interleukin-9:Interleukin-9 receptor (IL9:IL9R). Mutation of IL9R phosphorylated tyrosine-116 abolished activation of STAT1, STAT3 and STAT5 (Demoulin et al. 1996, Bauer et al. 1998). Other residues near this position are involved in determining which STAT binds to the receptor (Demoulin et al. 1999).
R-HSA-8985943 (Reactome) Phosphorylated Signal transducer and activator of transcription 1-alpha/beta (STAT1) homodimerizes. Following IL9 induced STAT activation, homodimers of tyrosine phosphorylated STAT1 have been identified (Bauer et al. 1998).
R-HSA-8985950 (Reactome) Phosphorylated Signal transducer and activator of transcription 5A/B (STAT5) homodimerizes.

Following IL9 induced STAT activation, homodimers of tyrosine phosphorylated STAT5 have been identified (Bauer et al. 1998).
R-HSA-8985966 (Reactome) Signal transducer and activator of transcription 1-alpha/beta (STAT1) and STAT3 dimerize.

Following IL9 induced STAT activation, heterodimers of tyrosine phosphorylated STAT1:STAT3 have been identified (Bauer et al. 1998).
R-HSA-8985973 (Reactome) Interleukin-9 receptor (IL9R) is phosphorylated after ligand-receptor interaction. IL9R tyrosine-116 is required for Interleukin-9 (IL9) mediated receptor tyrosine phosphorylation and STAT activation (Demoulin et al. 1996, Bauer et al. 1998).

This is a black box event because it is has not been established which of the JAKs phosphorylates IL9R.
R-HSA-8985981 (Reactome) The Signal transducer and activator of transcription 1-alpha/beta (STAT1) -Signal transducer and activator of transcription 3 (STAT3) complex translocates from the cytosol to the nucleus. Interleukin-9 (IL9) stimulation induces STAT3 nuclear translocation and binding in vivo to the Eotaxin (CCL11) promoter (Yamasaki et al. 2010, Gounni et al. 2004). Interleukin-9 (IL9) stimulation induces mucin5AC, junB and c-myc transcription (Longphre et al. 1999, Kang et al, 1995).

This is a black box event because this evidence shows STAT3 translocation, but not translocation of a STAT1:STAT3 dimer.
R-HSA-8985988 (Reactome) Signal transducer and activator of transcription 1-alpha/beta (STAT1), STAT3, and STAT5A/STAT5B (collectively termed STAT5) are tyrosine phosphorylated in tyrosine residues 701, 705 and 649 respectively, in response to IL9 stimulation (Nizsalóczki et al. 2014, Yamasaki et al. 2010, Demoulin et al. 2001).
R-HSA-9011748 (Reactome) Interleukin-9 receptor (IL9R) binds Tyrosine-protein kinase JAK1 (JAK1); this association is believed to be constitutive (Demoulin et al. 1996, Zhu et al 1997). The association is ascribed to a 98-residue juxta-membrane region within the BOX1 motif of the receptor that contains a Pro-X-Pro sequence preceded by a cluster of hydrophobic residues, a consensus sequence shared by many other cytokine receptors e.g. IL4R, IL7R, IL3R (Murakami et al. 1991, Zhu et al 1997).
STAT1,STAT3,STAT5A,STAT5BR-HSA-8985929 (Reactome)
p-STAT5A,p-STAT5B dimerArrowR-HSA-8985950 (Reactome)
p-Y-STAT1 dimerArrowR-HSA-8985943 (Reactome)
p-Y649-STAT5A, p-STAT5BR-HSA-8985950 (Reactome)
p-Y701-STAT1,p-Y705-STAT3,p-Y649-STAT5A,p-STAT5BArrowR-HSA-8985900 (Reactome)
p-Y701-STAT1:p-Y705-STAT3ArrowR-HSA-8985966 (Reactome)
p-Y701-STAT1:p-Y705-STAT3ArrowR-HSA-8985981 (Reactome)
p-Y701-STAT1:p-Y705-STAT3R-HSA-8985981 (Reactome)
p-Y701-STAT1R-HSA-8985943 (Reactome)
p-Y701-STAT1R-HSA-8985966 (Reactome)
p-Y705-STAT3R-HSA-8985966 (Reactome)
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