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Immune response IL-2 activation and signaling pathway

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Immune response IL-2 activation and signaling pathway

IL-2 activation and signaling pathway

Interleukin-2 ( IL-2 ) is a T-Cell-derived cytokine important in the regulationof 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 complexconsisting of an alpha ( IL-2R alpha chain ), beta ( IL-2R beta chain ) andgamma ( IL-2R gamma chain ) subunits. The IL-2R alpha chain primarilyincreases the affinity of ligand binding, whereas IL-2R beta chain and IL-2Rgamma chain participate in both ligand binding, and signal transduction [1].

IL-2 receptor activates several different pathways that mediate the flow ofmitogenic and survival-promoting signals [2].

Janus Kinases-1 and -3 ( JAK1 and JAK3 ) that are associated withIL-2R beta chain and IL-2R gamma chain, respectively, are activated afterbinding of IL-2 to its receptor [3], [4]. Phosphorylationof the cytoplasmic domains of IL-2 receptor provides docking sites for theJAK1 and JAK3. The latter autophosphorylate and provide docking sites forand phosphorylate Signal transducer and activator of transcription-5 ( STAT5A,STAT5 ). Phosphorylation induces dimerization and nuclear translocation ofSTAT5 complexes, where they promote transcription of specific target genes, e.g.,Cytokine inducible SH2-containing protein ( CISH ) that negatively modulatesSTAT5 activation [5], [1].

IL-2 receptor complex also binds Spleen tyrosine kinase ( Syk )and lymphocyte-specific protein tyrosine kinase ( Lck ) that are activateddownstream of JAK1 and JAK3, respectively [6]. Lck iscritical for the induction of c-Fos gene. Activation of Syk results in theinduction of the c-Myc gene. JAK3 is required for the induction of bothc-Fos and c-Myc genes [7], [8], [9],[10].

Suppressor of cytokine signaling 1 ( SOCS1 ) is an IL-2 -inducedinhibitor of IL-2 signaling that associates with JAK1 and inhibitsJAK1 kinase activity [11].

Protein tyrosine phosphatase, non-receptor type 6 ( SHP-1 ) dephosphorylatesJAK1 and acts as a negative regulator of IL-2 receptor/ JAK1signaling [12].

IL-2 receptor signaling also activates Phosphatidylinositol 3-kinase ( PI3Kreg class IA (p85)/ PI3K cat class IA ) which catalyzes phosphorylation ofPhosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ) [13]. Thissecond messenger recruits molecules such as 3-Phosphoinositide dependent protein kinase-1( PDK (PDPK1) ) and v-Akt murine thymoma viral oncogene homolog ( AKT ) tothe cell membrane [14], [15], [16]. AKTsignaling stimulates Nuclear factor-kappa B ( NF-kB ) activity by up-regulatingI-kappaB ( I-kB ) degradation via phosphorylation of I-kappaB kinase alpha (IKK-alpha ), a subunit of I-kappaB kinase complex ( IKK (cat) ), therebyallowing the transcription of NF-kB target genes, such as genes encoding proteinsinvolved in promoting cell survival, as well as transcription of IL-2R alpha chainand IL-2 itself [17], [18], [19], [20], [21].

IL-2 stimulates SHC (Src homology 2 domain containing) transforming protein 1 (Shc )/ Growth factor receptor-bound protein 2 ( GRB2 )/ Son of sevenlesshomologs ( 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]. This pathway induces activation of transcription factors, includingElk-1, c-Fos, c-Jun/c-Fos and AP-1 that play a criticalrole in IL-2 gene expression [23], [24], [25].

Protein tyrosine phosphatase, non-receptor type 11 ( SHP-2 ) associates withPI3K reg class IA (p85), GRB2 and GRB2-associated binding protein (GAB2 ), and activates ERK1/2 pathway [26], [27],[28].

IL-2 gene expression in antigen-activated T cells plays a critical role inorchestrating the immune responses. IL-2 gene expression is controlled at multiplelevels. In an autocrine fashion, the antigen-primed T helper cell secretes IL-2,stimulating itself as well as other neighboring T cells [17], [19],[29].

Up-regulation of IL-2 gene expression is also the major endpoint of signalingby the T cell antigen receptor (TCR). In normal T cells, engagement of TCR-CD3 complexesand costimulation by CD28 lead to the stimulation of multiple pathways followed byactivation of transcription factors, including NF-kB, nuclear factor of activatedT-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 genetranscription [30], [31], [29]. High mobility groupAT-hook 1 ( HMGI/Y ) can facilitate the formation of this functional complex oftranscription factors, activating IL-2 gene expression [32].

Transforming growth factor-beta (TGF-beta) suppresses IL-2 gene expression in Tcells via SMAD family ( SMAD3 and SMAD4 )-dependent signaling [33], [34], [35]. Transducer of ERBB2 1 ( Tob1 )associates with SMAD4 and exerts the inhibitory effect on IL-2transcription by enhancement of SMAD4 DNA-binding on the negative regulatoryelement of the IL-2 promoter [33].