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, 18.104.22.168, MEK2, IL-4, IGHG4, Eotaxin, IL-4R type I, IL4RA, CD23, IGHE, Shc, mTOR, GSK3 beta, MEK1, c-Raf-1
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 ) , , , , , , , , .
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 , .
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 , .
IL-4 engagement of IL-4R type I results in tyrosine phosphorylation of Janus kinases 1 and 3 ( JAK1 and JAK3 ) , , . JAK1 phosphorylates Signal transducer and activator of transcription 6 ( STAT6 ), which dimerizes and is translocated to the nucleus , , , , . 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 ) , , , , , , , , , , , .
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 , .
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) ) , , , , .
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 , , , , .
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 , .
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 ) , , , , , .