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 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].

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

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], [4]. 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 [1], [5].

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]. 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], [8], [9], [10].

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].

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

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]. 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], [15], [16]. 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], [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 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]. 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], [24], [25].

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], [27], [28].

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], [19], [29].

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 [29], [30], [31]. 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].

Transforming growth factor-beta (TGF-beta) suppresses IL-2 gene expression in T cells 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-2 transcription by enhancement of SMAD4 DNA-binding on the negative regulatory element of the IL-2 promoter [33].

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