JAK1, PI3K cat class IA, SOCS3, NF-AT1, Syk, IL-2 receptor, Calcineurin A, 22.214.171.124, CISH, ELF1, IKK-alpha, c-Fos, Elk-1, AKT, IL-2R alpha chain, Shc, MEK1, GAB2, STAT5, PI3K reg class IA (p85), HMGI/Y, IL-2R beta chain, c-Jun/c-Fos, SHPS-1, STAT5A, JAK3, GRB2, IL-2R gamma chain, SMAD4, IL-2, NF-kB, SHP-2, c-Raf-1, SHP-1, SOS, AP-1, PDK (PDPK1), EGR1, ERK1/2, SMAD3, PtdIns(3,4,5)P3, Lck, c-Myc, MEK2, IKK (cat), H-Ras, I-kB, PtdIns(4,5)P2, Tob1
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 Phosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ) . 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 Elk-1, c-Fos, c-Jun/c-Fos and AP-1 that play a critical role in IL-2 gene expression , , .
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 ( 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 , , . High mobility group AT-hook 1 ( HMGI/Y ) can facilitate the formation of this functional complex of transcription factors, activating IL-2 gene expression .
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 .