Interleukin-4 and Interleukin-13 signaling (Homo sapiens)
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Description
Interleukin-13 (IL13) is an immunoregulatory cytokine secreted predominantly by activated Th2 cells. It is a key mediator in the pathogenesis of allergic inflammation. IL13 shares many functional properties with IL4, stemming from the fact that they share a common receptor subunit. IL13 receptors are expressed on human B cells, basophils, eosinophils, mast cells, endothelial cells, fibroblasts, monocytes, macrophages, respiratory epithelial cells, and smooth muscle cells, but unlike IL4, not T cells. Thus IL13 does not appear to be important in the initial differentiation of CD4 T cells into Th2 cells, rather it is important in the effector phase of allergic inflammation (Hershey et al. 2003).
IL4 and IL13 induce “alternative activation� of macrophages, inducing an anti-inflammatory phenotype by signaling through IL4R alpha in a STAT6 dependent manner. This signaling plays an important role in the Th2 response, mediating anti-parasitic effects and aiding wound healing (Gordon & Martinez 2010, Loke et al. 2002)
There are two types of IL4 receptor complex (Andrews et al. 2006). Type I IL4R (IL4R1) is predominantly expressed on the surface of hematopoietic cells and consists of IL4R and IL2RG, the common gamma chain. Type II IL4R (IL4R2) is predominantly expressed on the surface of nonhematopoietic cells, it consists of IL4R and IL13RA1 and is also the type II receptor for IL13. (Obiri et al. 1995, Aman et al. 1996, Hilton et al. 1996, Miloux et al. 1997, Zhang et al. 1997). The second receptor for IL13 consists of IL4R and Interleukin-13 receptor alpha 2 (IL13RA2), sometimes called Interleukin-13 binding protein (IL13BP). It has a high affinity receptor for IL13 (Kd = 250 pmol/L) but is not sufficient to render cells responsive to IL13, even in the presence of IL4R (Donaldson et al. 1998). It is reported to exist in soluble form (Zhang et al. 1997) and when overexpressed reduces JAK-STAT signaling (Kawakami et al. 2001). It's function may be to prevent IL13 signalling via the functional IL4R:IL13RA1 receptor. IL13RA2 is overexpressed and enhances cell invasion in some human cancers (Joshi & Puri 2012).
The first step in the formation of IL4R1 (IL4:IL4R:IL2RB) is the binding of IL4 with IL4R (Hoffman et al. 1995, Shen et al. 1996, Hage et al. 1999). This is also the first step in formation of IL4R2 (IL4:IL4R:IL13RA1). After the initial binding of IL4 and IL4R, IL2RB binds (LaPorte et al. 2008), to form IL4R1. Alternatively, IL13RA1 binds, forming IL4R2. In contrast, the type II IL13 complex (IL13R2) forms with IL13 first binding to IL13RA1 followed by recruitment of IL4R (Wang et al. 2009).
Crystal structures of the IL4:IL4R:IL2RG, IL4:IL4R:IL13RA1 and IL13:IL4R:IL13RA1 complexes have been determined (LaPorte et al. 2008). Consistent with these structures, in monocytes IL4R is tyrosine phosphorylated in response to both IL4 and IL13 (Roy et al. 2002, Gordon & Martinez 2010) while IL13RA1 phosphorylation is induced only by IL13 (Roy et al. 2002, LaPorte et al. 2008) and IL2RG phosphorylation is induced only by IL4 (Roy et al. 2002).
Both IL4 receptor complexes signal through Jak/STAT cascades. IL4R is constitutively-associated with JAK2 (Roy et al. 2002) and associates with JAK1 following binding of IL4 (Yin et al. 1994) or IL13 (Roy et al. 2002). IL2RG constitutively associates with JAK3 (Boussiotis et al. 1994, Russell et al. 1994). IL13RA1 constitutively associates with TYK2 (Umeshita-Suyama et al. 2000, Roy et al. 2002, LaPorte et al. 2008, Bhattacharjee et al. 2013).
IL4 binding to IL4R1 leads to phosphorylation of JAK1 (but not JAK2) and STAT6 activation (Takeda et al. 1994, Ratthe et al. 2007, Bhattacharjee et al. 2013).
IL13 binding increases activating tyrosine-99 phosphorylation of IL13RA1 but not that of IL2RG. IL4 binding to IL2RG leads to its tyrosine phosphorylation (Roy et al. 2002). IL13 binding to IL4R2 leads to TYK2 and JAK2 (but not JAK1) phosphorylation (Roy & Cathcart 1998, Roy et al. 2002).
Phosphorylated TYK2 binds and phosphorylates STAT6 and possibly STAT1 (Bhattacharjee et al. 2013).
A second mechanism of signal transduction activated by IL4 and IL13 leads to the insulin receptor substrate (IRS) family (Kelly-Welch et al. 2003). IL4R1 associates with insulin receptor substrate 2 and activates the PI3K/Akt and Ras/MEK/Erk pathways involved in cell proliferation, survival and translational control. IL4R2 does not associate with insulin receptor substrate 2 and consequently the PI3K/Akt and Ras/MEK/Erk pathways are not activated (Busch-Dienstfertig & González-RodrÃguez 2013).
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genes for extracellular
proteinsgenes for plasma
membrane proteinsextracellular
proteinsextracellular
proteinsgenes for extracellular
proteinsgenes for cytosolic
proteinsgenes for nuclear
proteinsgenes for plasma
membrane proteinsplasma membrane
proteinsextracellular
protein genesextracellular
proteinsplasma membrane
protein genesplasma membrane
proteinsdimer,p-Y705-STAT3 dimer,p-Y641-STAT6
dimerdimer,p-Y705-STAT3 dimer,p-Y641-STAT6
dimerAnnotated Interactions
genes for extracellular
proteinsgenes for plasma
membrane proteinsextracellular
proteinsIL4R contains 5 conserved tyrosine residues, Y497, Y575, Y603, Y631, and Y713, which can all play a role in signaling through this receptor. Structure-function analyses have revealed that Y497 is part of the IL4R motif that is necessary for the recruitment of IRS1 and IRS2 to IL4R and is critical for IL4-dependent cell proliferation (Keegan et al. 1994). STAT6 signaling requires one of tyrosines Y575, Y603, and Y631 (Ryan et al. 1996). Y713 is part of an immunotyrosine-based inhibitory motif (ITIM) shown to be important in the negative regulation of IL4 and IL13 responses (Kashiwada et al. 2001).
Binding and phosphorylation of STAT3 has been reported in response to IL13 (Rahaman et al. 2005, Bhattacharjee et al. 2013) but not IL4 (Friedrich et al. 1999), suggesting that STAT3 binding might depend on IL13RA, but recently STAT3 was reported to associate with IL4R and be phosphorylated by Janus kinase 2 (JAK2) (Umeshita-Suyama et al. 2000, Bhattacharjee et al. 2013).
STAT1 is activated in response to IL13 (Wang et al. 2004) and reported to bind IL13RA1 and be phosphorylated by TYK2 (Bhattacharjee et al. 2013).
According to the classical model, phosphorylated Signal transducer and activator of transcription (STAT) monomers associate in an active dimer form, which is stabilized by the reciprocal interactions between a phosphorylated tyrosine residue of one and the SH2 domain of the other monomer (Shuai et al. 1994). These dimers then translocate to the nucleus (Akira et al. 1994). Recently an increasing number of studies have demonstrated the existence of STAT dimers in unstimulated cell states and the capability of STATs to exert biological functions independently of phosphorylation (Braunstein et al. 2003, Li et al. 2008, Santos & Costas-Pereira 2011). As phosphorylation of STATs is not unequivocally required for its subsequent translocation to the nucleus, this event is shown as an uncertain process.
Recently, STATs have been shown to shuttle freely between the cytoplasm and the nucleus, independent of tyrosine phosphorylation (Liu et al. 2005, Li 2008, Reich 2013). Binding of unphosphorylated STAT3 to DNA has been reported (Nkansah et al. 2013). As it is not clear what triggers nuclear accumulation of STATs in response to IL13, this event is shown as an uncertain process.
This is a black box event because the mechanism of gene regulation is not fully defined.
Genes for extracellular proteins that are upregulated by STAT3 include Lipopolysaccharide-binding protein (LBP) (Schumann et al. 1996), IL10 (Schaefer et al. 2009), IL23A (Kortylewski et al. 2009), Transforming growth factor beta-1 (TGFB1) (Kinjyo et al. 2006), Matrix metalloproteinase-1 (MMP1, Interstitial collagenase) (Itoh et al. 2006), MMP2 (Xie et al. 2004), MMP3 (Liu et al. 2013), MMP9 (Song et al. 2009), Neutrophil gelatinase-associated lipocalin (LCN2) (Jung et al. 2012, Xu et al. 2015), Pro-opiomelanocortin (POMC) (Bosquet et al. 2000), Serum amyloid A-1 protein (SAA1) (Hagihara et al. 2005), Vascular endothelial growth factor A (VEGFA) (Niu et al. 2002), Fibroblast growth factor 2 (FGF2) (Huang et al. 2013), Hepatocyte growth factor (HGF) (Hung & Elliot 2001), IL17A, IL17F (Durant et al. 2010) and Metalloproteinase inhibitor 1 (TIMP1) (Adamson et al. 2013).
This is a black box event because the mechanism of gene regulation is not fully defined.
extracellular
proteinsgenes for extracellular
proteinsgenes for cytosolic
proteinsgenes for nuclear
proteinsgenes for plasma
membrane proteinsplasma membrane
proteinsextracellular
protein genesextracellular
proteinsplasma membrane
protein genesplasma membrane
proteinsdimer,p-Y705-STAT3 dimer,p-Y641-STAT6
dimerdimer,p-Y705-STAT3 dimer,p-Y641-STAT6
dimerdimer,p-Y705-STAT3 dimer,p-Y641-STAT6
dimer