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).
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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.
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).
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).
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).
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).
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).
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).
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.
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.
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).
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).
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This is a black box event since the details about of the phosphorylated region could be incomplete.
Annotated Interactions
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).
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).
Following IL9 induced STAT activation, homodimers of tyrosine phosphorylated STAT5 have been identified (Bauer et al. 1998).
Following IL9 induced STAT activation, heterodimers of tyrosine phosphorylated STAT1:STAT3 have been identified (Bauer et al. 1998).
This is a black box event because it is has not been established which of the JAKs phosphorylates IL9R.
This is a black box event because this evidence shows STAT3 translocation, but not translocation of a STAT1:STAT3 dimer.