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) , , , , , , , , , , , .
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 , , .
In response to IL-4 signaling,
JAK1 phosphorylates Inositol polyphosphate-5-phosphatase
145kDa (SHIP) followed by positive regulation of cell
proliferation , .
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(3,4,5)P3 activates 3-Phosphoinositide dependent
protein kinase-1 (PDK (PDPK1)) and v-Akt murine thymoma
viral oncogene homolog (AKT(PKB)) , , , , .
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 , , .
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) , , , , , .
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