IL-2 activation and signaling pathway
Interleukin-2 (IL-2) is a T-Cell-derived cytokine
important in the regulation of growth and differentiation of T-Cells, B-Cells, natural
killer cells, glioma cells, and cells of the monocyte lineage.
IL-2 signaling is mediated by a multichain
IL-2 receptor complex consisting of an alpha
(IL-2R alpha chain), beta (IL-2R beta
chain) and gamma (IL-2R gamma chain)
subunits. The IL-2R alpha chain primarily increases the
affinity of ligand binding, whereas IL-2R beta chain and
IL-2R gamma chain participate in both ligand binding, and
signal transduction .
IL-2 receptor activates several different pathways that
mediate the flow of mitogenic and survival-promoting signals .
Janus Kinases-1 and -3 (JAK1 and
JAK3) that are associated with IL-2R beta
chain and IL-2R gamma chain, respectively,
are activated after binding of IL-2 to its receptor , . Phosphorylation of the cytoplasmic domains of
IL-2 receptor provides docking sites for the
JAK1 and JAK3. The latter
autophosphorylate and provide docking sites for and phosphorylate Signal
transducer and activator of transcription-5 (STAT5A,
STAT5). Phosphorylation induces dimerization and nuclear
translocation of STAT5 complexes, where they promote
transcription of specific target genes, e.g., Cytokine inducible SH2-containing protein
(CISH) that negatively modulates
STAT5 activation , .
IL-2 receptor complex also
binds Spleen tyrosine kinase (Syk) and lymphocyte-specific
protein tyrosine kinase (Lck) that are activated downstream
of JAK1 and JAK3, respectively
. Lck is critical for the induction of
c-Fos gene. Activation of Syk
results in the induction of the c-Myc gene.
JAK3 is required for the induction of both
c-Fos and c-Myc genes , , , .
Suppressor of cytokine signaling 1 (SOCS1) is an
IL-2-induced inhibitor of IL-2
signaling that associates with JAK1 and inhibits
JAK1 kinase activity .
Protein tyrosine phosphatase, non-receptor type 6 (SHP-1)
dephosphorylates JAK1 and acts as a negative regulator of
IL-2 receptor/ JAK1 signaling
IL-2 receptor signaling also activates
Phosphatidylinositol 3-kinase (PI3K reg class IA (p85)/
PI3K cat class IA) which catalyzes phosphorylation of
. This second messenger recruits molecules such as 3-Phosphoinositide
dependent protein kinase-1 (PDK (PDPK1)) and v-Akt murine
thymoma viral oncogene homolog (AKT) to the cell membrane
, , . AKT
signaling stimulates Nuclear factor-kappa B (NF-kB) activity
by up-regulating 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, such as
genes encoding proteins involved in promoting cell survival, as well as transcription of
IL-2R alpha chain and IL-2
itself , , , , .
IL-2 stimulates SHC (Src homology 2 domain containing)
transforming protein 1 (Shc)/ Growth factor receptor-bound
protein 2 (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) signaling . This pathway induces activation of transcription factors, including
c-Jun/c-Fos and AP-1
that play a critical role in
IL-2 gene expression , , .
Protein tyrosine phosphatase, non-receptor type 11
(SHP-2) associates with PI3K reg class IA
(p85), GRB2 and GRB2-associated binding
protein (GAB2), and activates ERK1/2
pathway , , .
IL-2 gene expression in antigen-activated T cells plays a
critical role in orchestrating the immune responses. IL-2
gene expression is controlled at multiple levels. In an autocrine fashion, the
antigen-primed T helper cell secretes IL-2, stimulating
itself as well as other neighboring T cells , , .
Up-regulation of IL-2 gene expression is also the major
endpoint of signaling by the T cell antigen receptor (TCR). In normal T cells, engagement
of TCR-CD3 complexes and costimulation by CD28 lead to the stimulation of multiple
pathways followed by activation of transcription factors, including
NF-kB, nuclear factor of activated T-cells cytoplasmic
calcineurin-dependent 2 (NF-AT1), Early growth response 1
(EGR1), E74-like factor 1
AP-1 and constitutively expressed POU class 2 homeobox 1
(Oct-1) regulate the IL-2
proximal promoter to drive IL-2 gene transcription , , . High mobility group AT-hook 1
(HMGI/Y) can facilitate the formation of this functional
complex of transcription factors, activating IL-2 gene
Transforming growth factor-beta (TGF-beta) suppresses
IL-2 gene expression in T cells via SMAD family
(SMAD3 and SMAD4)-dependent
signaling , , . Transducer of ERBB2 1
(Tob1) associates with SMAD4
and exerts the inhibitory effect on IL-2 transcription by
enhancement of SMAD4 DNA-binding on the negative regulatory
element of the IL-2 promoter .
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