Pathway Map Details
Immune response_IL-2 activation and signaling pathway
Object list (links open in MetaCore):
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 .
- Cacalano NA, Johnston JA
Interleukin-2 signaling and inherited immunodeficiency. American journal of human genetics 1999 Aug;65(2):287-93
- Benczik M, Gaffen SL
The interleukin (IL)-2 family cytokines: survival and proliferation signaling pathways in T lymphocytes. Immunological investigations 2004 May;33(2):109-42
- Liu KD, Gaffen SL, Goldsmith MA, Greene WC
Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation. Current biology : CB 1997 Nov 1;7(11):817-26
- Zhu MH, Berry JA, Russell SM, Leonard WJ
Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3 to Il-2Rbeta. The Journal of biological chemistry 1998 Apr 24;273(17):10719-25
- Matsumoto A, Masuhara M, Mitsui K, Yokouchi M, Ohtsubo M, Misawa H, Miyajima A, Yoshimura A
CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood 1997 May 1;89(9):3148-54
- Zhou YJ, Magnuson KS, Cheng TP, Gadina M, Frucht DM, Galon J, Candotti F, Geahlen RL, Changelian PS, O'Shea JJ
Hierarchy of protein tyrosine kinases in interleukin-2 (IL-2) signaling: activation of syk depends on Jak3; however, neither Syk nor Lck is required for IL-2-mediated STAT activation. Molecular and cellular biology 2000 Jun;20(12):4371-80
- Minami Y, Nakagawa Y, Kawahara A, Miyazaki T, Sada K, Yamamura H, Taniguchi T
Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathway. Immunity 1995 Jan;2(1):89-100
- Miyazaki T, Taniguchi T
Coupling of the IL2 receptor complex with non-receptor protein tyrosine kinases. Cancer surveys 1996;27:25-40
- G??mez J, Gonz??lez A, Mart??nez-A C, Rebollo A
IL-2-induced cellular events. Critical reviews in immunology 1998;18(3):185-220
- Lord JD, McIntosh BC, Greenberg PD, Nelson BH
The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. Journal of immunology (Baltimore, Md. : 1950) 2000 Mar 1;164(5):2533-41
- Sporri B, Kovanen PE, Sasaki A, Yoshimura A, Leonard WJ
JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling. Blood 2001 Jan 1;97(1):221-6
- Migone TS, Cacalano NA, Taylor N, Yi T, Waldmann TA, Johnston JA
Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells. Proceedings of the National Academy of Sciences of the United States of America 1998 Mar 31;95(7):3845-50
- Migone TS, Rodig S, Cacalano NA, Berg M, Schreiber RD, Leonard WJ
Functional cooperation of the interleukin-2 receptor beta chain and Jak1 in phosphatidylinositol 3-kinase recruitment and phosphorylation. Molecular and cellular biology 1998 Nov;18(11):6416-22
- Datta SR, Brunet A, Greenberg ME
Cellular survival: a play in three Akts. Genes & development 1999 Nov 15;13(22):2905-27
- Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM, Medema RH
The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. Journal of immunology (Baltimore, Md. : 1950) 2002 May 15;168(10):5024-31
- Zeiser R, Negrin RS
Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. Cell cycle (Georgetown, Tex.) 2008 Feb 15;7(4):458-62
- H??mar A, Cereghini S, Cornet V, Blank V, Isra??l A, Greene WC, Dautry-Varsat A
Kappa B binding proteins are constitutively expressed in an IL-2 autocrine human T cell line. Journal of immunology (Baltimore, Md. : 1950) 1991 Apr 1;146(7):2409-16
- Pimentel-Mui??os FX, Mazana J, Fresno M
Regulation of interleukin-2 receptor alpha chain expression and nuclear factor.kappa B activation by protein kinase C in T lymphocytes. Autocrine role of tumor necrosis factor alpha. The Journal of biological chemistry 1994 Sep 30;269(39):24424-9
- Kahn-Perl??s B, Lipcey C, L??cine P, Olive D, Imbert J
Temporal and subunit-specific modulations of the Rel/NF-kappaB transcription factors through CD28 costimulation. The Journal of biological chemistry 1997 Aug 29;272(35):21774-83
- Kane LP, Shapiro VS, Stokoe D, Weiss A
Induction of NF-kappaB by the Akt/PKB kinase. Current biology : CB 1999 Jun 3;9(11):601-4
- Lauder A, Castellanos A, Weston K
c-Myb transcription is activated by protein kinase B (PKB) following interleukin 2 stimulation of Tcells and is required for PKB-mediated protection from apoptosis. Molecular and cellular biology 2001 Sep;21(17):5797-805
- Ravichandran KS, Burakoff SJ
The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. The Journal of biological chemistry 1994 Jan 21;269(3):1599-602
- Mortellaro A, Songia S, Gnocchi P, Ferrari M, Fornasiero C, D'Alessio R, Isetta A, Colotta F, Golay J
New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation. Journal of immunology (Baltimore, Md. : 1950) 1999 Jun 15;162(12):7102-9
- Cianferoni A, Massaad M, Feske S, de la Fuente MA, Gallego L, Ramesh N, Geha RS
Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott-Aldrich syndrome. The Journal of allergy and clinical immunology 2005 Dec;116(6):1364-71
- Kim HP, Imbert J, Leonard WJ
Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine & growth factor reviews 2006 Oct;17(5):349-66
- Gadina M, Sudarshan C, O'Shea JJ
IL-2, but not IL-4 and other cytokines, induces phosphorylation of a 98-kDa protein associated with SHP-2, phosphatidylinositol 3'-kinase, and Grb2. Journal of immunology (Baltimore, Md. : 1950) 1999 Feb 15;162(4):2081-6
- Arnaud M, Mzali R, Gesbert F, Crouin C, Guenzi C, Vermot-Desroches C, Wijdenes J, Courtois G, Bernard O, Bertoglio J
Interaction of the tyrosine phosphatase SHP-2 with Gab2 regulates Rho-dependent activation of the c-fos serum response element by interleukin-2. The Biochemical journal 2004 Sep 1;382(Pt 2):545-56
- Arnaud M, Crouin C, Deon C, Loyaux D, Bertoglio J
Phosphorylation of Grb2-associated binder 2 on serine 623 by ERK MAPK regulates its association with the phosphatase SHP-2 and decreases STAT5 activation. Journal of immunology (Baltimore, Md. : 1950) 2004 Sep 15;173(6):3962-71
- Gaffen SL, Liu KD
Overview of interleukin-2 function, production and clinical applications. Cytokine 2004 Nov 7;28(3):109-23
- Thompson CB, Wang CY, Ho IC, Bohjanen PR, Petryniak B, June CH, Miesfeldt S, Zhang L, Nabel GJ, Karpinski B
cis-acting sequences required for inducible interleukin-2 enhancer function bind a novel Ets-related protein, Elf-1. Molecular and cellular biology 1992 Mar;12(3):1043-53
- Decker EL, Nehmann N, Kampen E, Eibel H, Zipfel PF, Skerka C
Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression. Nucleic acids research 2003 Feb 1;31(3):911-21
- Himes SR, Reeves R, Attema J, Nissen M, Li Y, Shannon MF
The role of high-mobility group I(Y) proteins in expression of IL-2 and T cell proliferation. Journal of immunology (Baltimore, Md. : 1950) 2000 Mar 15;164(6):3157-68
- Tzachanis D, Freeman GJ, Hirano N, van Puijenbroek AA, Delfs MW, Berezovskaya A, Nadler LM, Boussiotis VA
Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nature immunology 2001 Dec;2(12):1174-82
- Nelson BH, Martyak TP, Thompson LJ, Moon JJ, Wang T
Uncoupling of promitogenic and antiapoptotic functions of IL-2 by Smad-dependent TGF-beta signaling. Journal of immunology (Baltimore, Md. : 1950) 2003 Jun 1;170(11):5563-70
- McKarns SC, Schwartz RH, Kaminski NE
Smad3 is essential for TGF-beta 1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. Journal of immunology (Baltimore, Md. : 1950) 2004 Apr 1;172(7):4275-84