Pathway Map Details

Immune response_IL-4 signaling pathway



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IKK-alpha, H-Ras, PDK (PDPK1), c-Fes, SOCS5, PI3K reg class IA, IgE, PtdIns(3,4,5)P3, IRS-1, IgG4, IRS-2, JAK1, SOS, GRB2, I-kB, AKT(PKB), GATA-3, NF-kB, ERK1/2, SOCS1, STAT6, Elk-1, IKK (cat), JAK3, IgG1, p70 S6 kinase1, IGHG1, PI3K cat class IA, SHIP, PtdIns(4,5)P2, 2.7.1.153, MEK2, IL-4, IGHG4, Eotaxin, IL-4R type I, IL4RA, CD23, IGHE, Shc, mTOR, GSK3 beta, MEK1, c-Raf-1

Description:

IL-4 signaling pathway

Interleukin-4 ( IL-4 ) is a T cell derived multifunctional cytokine that plays a critical role in the regulation of immune responses. IL-4 induces Th2 (T helper 2) differentiation, causes macrophage suppression, and stimulates B cell production of Immunoglobulins E, G1 and G4 ( IgE, IgG1 and IgG4 ) [1], [2], [3], [4], [5], [6], [7], [8], [9].

IL-4 can stimulate two receptors, type I and type II. IL-4 receptor type I ( IL-4R type I ) consists of two subunits, an alpha chain ( IL4RA ) and a common gamma chain, shared by other cytokines of the IL-2 family [10], [11].

IL-4 binding to IL-4R type I activates several different pathways followed by B cell proliferation, survival of T and B cells, and the production of chemokines important for the recruitment of cells that participate in allergic immune responses [4], [12].

IL-4 engagement of IL-4R type I results in tyrosine phosphorylation of Janus kinases 1 and 3 ( JAK1 and JAK3 ) [13], [14], [15]. JAK1 phosphorylates Signal transducer and activator of transcription 6 ( STAT6 ), which dimerizes and is translocated to the nucleus [16], [17], [18], [19], [9]. In the nucleus, STAT6 promotes transcription of target genes, including Suppressor of cytokine signaling 1 ( SOCS1 ), IL4RA, Chemokine (C-C motif) ligand 11 ( Eotaxin ), GATA binding protein 3 ( GATA-3 ), Fc fragment of IgE, low affinity II, receptor for ( CD23 ), Immunoglobulin heavy constant epsilon ( IGHE ), Immunoglobulin heavy constant gamma 1 ( IGHG1 ) and Immunoglobulin heavy constant gamma 4 ( IGHG4 ) [16], [20], [21], [22], [23], [24], [25], [2], [26], [27], [28], [29].

Interaction of SOCS1 with JAK1, and association of Suppressor of cytokine signaling 5 ( SOCS5 ) with IL-4R type I result in the inhibition of IL-4 -mediated STAT6 activation [30], [31], [32].

In response to IL-4 signaling, JAK1 phosphorylates Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) followed by positive regulation of cell proliferation [33], [30].

JAK1 and JAK3 also phosphorylate two adapter molecules, Insulin receptor substrate 1 and 2 ( IRS-1 and IRS-2 ), leading to the activation of Phosphatidylinositol 3-kinase (PI3K) and Mitogen-activated protein (MAP) pathways [34], [35].

Phosphorylated IRS-1 and IRS-2 bind to and activate the PI3K regulatory subunit ( PI3K reg class IA ), which stimulates the PI3K catalytic subunit ( PI3K cat class IA ), generating Phosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ) from Phosphatidylinositol-4,5-bisphosphate ( PtdIns (4,5)P2 ). PtdIns(3,4,5)P3 activates 3-Phosphoinositide dependent protein kinase-1 ( PDK (PDPK1) ) and v-Akt murine thymoma viral oncogene homolog ( AKT(PKB) ) [36], [37], [18], [38], [39].

Association of Feline sarcoma oncogene ( c-Fes ) with IL-4R type I and with PI3K reg class IA upon IL-4 stimulation can also induce PI3K activation [40], [41], [42].

The downstream effectors of PI3K cat class IA/ PDK (PDPK1) and AKT(PKB) signaling, such as Ribosomal protein S6 kinase 70kDa polypeptide 1 ( p70S6K ), FK506 binding protein 12-rapamycin associated protein 1 ( mTOR ) and Glycogen synthase kinase 3 beta ( GSK3 beta ), mediate the effect of PI3K on cell survival by preventing apoptosis and stimulating cell growth and proliferation [43], [44], [39], [45], [46].

AKT also stimulates Nuclear factor-kappa B ( NF-kB ) activity by upregulating I-kappaB ( I-kB ) degradation via phosphorylation of I-kappaB kinase alpha ( IKK-alpha ), a subunit of I-kappaB kinase complex ( IKK (cat) ), thereby allowing the transcription of NF-kB target genes [47], [48].

IRS-1 and IRS-2 also activate Growth factor receptor-bound protein 2 ( GRB2 ), followed by stimulation of the MAP pathway: GRB2/ Son of sevenless homologs ( SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras )/ v-Raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ Extracellular signal-regulated kinase 1 and 2 ( ERK1/2 ). This pathway induces activation of transcription factors, including ELK1 member of ETS oncogene family ( Elk-1 ) [49], [50], [37], [51], [52], [19].

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