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      Immune response_IL-2 activation and signaling pathway



view in full size </maps/430_map.png> | open in MetaCore
<http://portal.genego.com/cgi/imagemap.cgi?id=430>


        Object list (links open in MetaCore):

JAK1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=431>,
PI3K cat class IA
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=2037>,
SOCS3
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=6152>,
NF-AT1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=4329>,
Syk
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=742>,
IL-2 receptor
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=400>,
Calcineurin A
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=-417087603>,
2.7.1.153
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=-1074992000>,
CISH
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=-1743877048>,
ELF1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=2805>,
IKK-alpha
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=2624>,
c-Fos
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=883>,
Elk-1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=241>,
AKT
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=592>,
IL-2R alpha chain
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=4449>,
Shc
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=2093>,
MEK1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=486>,
GAB2
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=9176>,
STAT5
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=724>,
PI3K reg class IA (p85)
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=-364786138>,
HMGI/Y
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=4330>,
IL-2R beta chain
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=6177>,
c-Jun/c-Fos
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=4351>,
SHPS-1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=700>,
STAT5A
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=-1471221921>,
JAK3
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=2440>,
GRB2
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=336>,
IL-2R gamma chain
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=8223>,
SMAD4
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=733>,
IL-2
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=398>,
NF-kB
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=522>,
SHP-2
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=699>,
c-Raf-1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=886>,
SHP-1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=698>,
SOS
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=738>,
AP-1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=35>, PDK
(PDPK1)
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=800>,
EGR1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=4387>,
ERK1/2
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=1071>,
SMAD3
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=4322>,
PtdIns(3,4,5)P3
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=631>,
Lck
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=467>,
c-Myc
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=2257>,
MEK2
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=487>,
IKK (cat)
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=385>,
H-Ras
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=680>,
I-kB
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=366>,
PtdIns(4,5)P2
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=589>,
Tob1
<http://portal.genego.com/cgi/regulation/regulation_info.cgi?id=-1964619858>



        Description:

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 [1] <#430_10417270>.

*IL-2 receptor* activates several different pathways that mediate the
flow of mitogenic and survival-promoting signals [2] <#430_15195693>.

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 [3] <#430_9382798>, [4]
<#430_9553136>. 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 [5] <#430_9129017>, [1]
<#430_10417270>.

*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 [6]
<#430_10825200>. *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 [7]
<#430_7600304>, [8] <#430_8909793>, [9] <#430_9637410>, [10]
<#430_10679091>.

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 [11] <#430_11133764>.

Protein tyrosine phosphatase, non-receptor type 6 ( *SHP-1* )
dephosphorylates *JAK1* and acts as a negative regulator of *IL-2
receptor*/ *JAK1* signaling [12] <#430_9520455>.

*IL-2 receptor* signaling also activates Phosphatidylinositol 3-kinase (
*PI3K reg class IA (p85)*/ *PI3K cat class IA* ) which catalyzes
phosphorylation of Phosphatidylinositol-3,4,5-trisphosphate (
*PtdIns(3,4,5)P3* ) [13] <#430_9774657>. 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 [14] <#430_10579998>, [15] <#430_11994454>, [16]
<#430_18235249>. *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 [17] <#430_2005404>, [18] <#430_7929104>,
[19] <#430_9268307>, [20] <#430_10359702>, [21] <#430_11486019>.

*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 [22] <#430_8294403>. This pathway induces
activation of transcription factors, including *Elk-1*, *c-Fos*,
*c-Jun/c-Fos* and *AP-1* that play a critical role in *IL-2* gene
expression [23] <#430_10358154>, [24] <#430_16337472>, [25] <#430_16911870>.

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 [26]
<#430_9973481>, [27] <#430_15170389>, [28] <#430_15356145>.

*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 [17] <#430_2005404>, [19] <#430_9268307>,
[29] <#430_15473953>.

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 ( *ELF1* ), *Elk-1*, *c-Fos*,
*c-Jun/c-Fos* and *AP-1*. Together, *NF-kB*, *NF* *-AT1*, *EGR1* *ELF1*,
*AP-1* and constitutively expressed POU class 2 homeobox 1 ( *Oct-1* )
regulate the *IL-2* proximal promoter to drive *IL-2* gene transcription
[30] <#430_1545787>, [31] <#430_12560487>, [29] <#430_15473953>. High
mobility group AT-hook 1 ( *HMGI/Y* ) can facilitate the formation of
this functional complex of transcription factors, activating *IL-2* gene
expression [32] <#430_10706706>.

Transforming growth factor-beta (TGF-beta) suppresses *IL-2* gene
expression in T cells via SMAD family ( *SMAD3* and *SMAD4* )-dependent
signaling [33] <#430_11694881>, [34] <#430_12759434>, [35]
<#430_15034041>. 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 [33] <#430_11694881>.


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