Pathway maps

Immune response_IL-3 activation and signaling pathway
Immune response_IL-3 activation and signaling pathway

Object List (links open in MetaCore):

c-Fos, SHIP, SOS, SOCS1, Calcineurin A (catalytic), Shc, ELF1, CISH, Elk-1, c-Jun/c-Fos, AP-1, Pim-1, c-Raf-1, GRB2, c-Fos, SHP-1, EGR1, ID1, Oncostatin M, IL-3 receptor, Oct-1, NF-AT1(NFATC2), IL-3, STAT5, SHP-2, MEK2, ERK1/2, JAK2, MEK1, H-Ras, SOCS3, PtdIns(3,4,5)P3

Description

IL-3 activation and signaling pathway

Interleukin-3 ( IL-3 ), also called a multi-lineage-colony stimulating factor, is produced by T cells and mast cells after activation with mitogens or antigens. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells [1].

IL-3 receptor is composed of two polypeptide chains, alpha and beta subunits. Both subunits contain extracellular domains. The alpha and beta subunits are associated only in the presence of ligand [2], [1].

Following IL-3 -induced hetero-dimerization, IL-3 receptor binds to multiple signal-transducing proteins, which include Janus kinase 2 ( JAK2 ), both isoforms of Signal transducer and activator of transcription 5 ( STAT5 ) and SHC transforming protein 1 ( Shc ) [3], [4], [5], [1].

Activated JAK2 phosphorylates STAT5. The latter dimerizes, translocates to the nucleus and activates transcription of genes, including Cytokine inducible SH2-containing protein ( CISH ), Oncostatin M, Inhibitor of DNA binding 1 dominant negative helix-loop-helix protein ( ID1 ), Pim-1 oncogene ( Pim-1 ), and v-Fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [6], [7], [8], [9]. Pim-1 interacts with Suppressors of cytokine signaling 1 and 3 ( SOCS1 and SOCS3 ) and potentiates their inhibitory effects on JAK2/ STAT5 signaling, most likely via phosphorylation-mediated stabilization of SOCS1 and SOCS3 proteins [10].

Protein tyrosine phosphatases SHP-1 and SHP-2 negatively regulate IL-3-driven cell survival and proliferation via dephosphorylation of IL-3 receptor and STAT5 [11], [12], [13].

SHP-2 tyrosine phosphatase plays multiple roles in IL-3 signal transduction. The association of Inositol polyphosphate-5-phosphatase ( SHIP ) with SHP-2 and association of SHP-2 with Growth factor receptor-bound protein 2 ( GRB2 ) can positively regulate cell growth and proliferation in response to IL-3 [14], [15], [16], [17].

Upon IL-3 stimulation, the adaptor molecule Shc is rapidly phosphorylated and associates with the phosphorylated IL-3 receptor. IL-3 stimulation also results in the activation of SHIP which associates with Shc and GRB2 that form a complex with Son of sevenless homologs ( SOS ), followed by the activation of 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 ), ERK1/2 and ELK1 member of ETS oncogene family ( Elk-1 ). Activation of this cascade culminates in the increased expression of transcription factors, including v-Fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [1].

IL-3 is expressed primarily in T cells in response to activation of T cell receptor signaling pathways. The T cell-specific expression of the IL-3 gene is controlled through the enhancer by cooperation between POU class 2 homeobox 1 ( Oct-1 ), Nuclear factor of activated T-cells calcineurin-dependent 2 ( NFAT-1 (NFATC2) ), Activator protein 1 ( AP-1 ), E74-like factor 1 ( ELF1 ) and Early growth response 1 ( EGR1 ) transcription factors [18], [19], [20], [21].

References:

  1. Reddy EP, Korapati A, Chaturvedi P, Rane S
    IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled. Oncogene 2000 May 15;19(21):2532-47
  2. Hara T, Miyajima A
    Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis. Stem cells (Dayton, Ohio) 1996 Nov;14(6):605-18
  3. Silvennoinen O, Witthuhn BA, Quelle FW, Cleveland JL, Yi T, Ihle JN
    Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Proceedings of the National Academy of Sciences of the United States of America 1993 Sep 15;90(18):8429-33
  4. Chin H, Nakamura N, Kamiyama R, Miyasaka N, Ihle JN, Miura O
    Physical and functional interactions between Stat5 and the tyrosine-phosphorylated receptors for erythropoietin and interleukin-3. Blood 1996 Dec 15;88(12):4415-25
  5. Bone H, Welham MJ
    Shc associates with the IL-3 receptor beta subunit, SHIP and Gab2 following IL-3 stimulation. Contribution of Shc PTB and SH2 domains. Cellular signalling 2000 Mar;12(3):183-94
  6. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A
    A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. The EMBO journal 1995 Jun 15;14(12):2816-26
  7. Yoshimura A, Ichihara M, Kinjyo I, Moriyama M, Copeland NG, Gilbert DJ, Jenkins NA, Hara T, Miyajima A
    Mouse oncostatin M: an immediate early gene induced by multiple cytokines through the JAK-STAT5 pathway. The EMBO journal 1996 Mar 1;15(5):1055-63
  8. Mui AL, Wakao H, Kinoshita T, Kitamura T, Miyajima A
    Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation. The EMBO journal 1996 May 15;15(10):2425-33
  9. Xu M, Nie L, Kim SH, Sun XH
    STAT5-induced Id-1 transcription involves recruitment of HDAC1 and deacetylation of C/EBPbeta. The EMBO journal 2003 Feb 17;22(4):893-904
  10. Peltola KJ, Paukku K, Aho TL, Ruuska M, Silvennoinen O, Koskinen PJ
    Pim-1 kinase inhibits STAT5-dependent transcription via its interactions with SOCS1 and SOCS3. Blood 2004 May 15;103(10):3744-50
  11. Yi T, Mui AL, Krystal G, Ihle JN
    Hematopoietic cell phosphatase associates with the interleukin-3 (IL-3) receptor beta chain and down-regulates IL-3-induced tyrosine phosphorylation and mitogenesis. Molecular and cellular biology 1993 Dec;13(12):7577-86
  12. Paling NR, Welham MJ
    Role of the protein tyrosine phosphatase SHP-1 (Src homology phosphatase-1) in the regulation of interleukin-3-induced survival, proliferation and signalling. The Biochemical journal 2002 Dec 15;368(Pt 3):885-94
  13. Chen J, Yu WM, Bunting KD, Qu CK
    A negative role of SHP-2 tyrosine phosphatase in growth factor-dependent hematopoietic cell survival. Oncogene 2004 Apr 29;23(20):3659-69
  14. Welham MJ, Dechert U, Leslie KB, Jirik F, Schrader JW
    Interleukin (IL)-3 and granulocyte/macrophage colony-stimulating factor, but not IL-4, induce tyrosine phosphorylation, activation, and association of SHPTP2 with Grb2 and phosphatidylinositol 3'-kinase. The Journal of biological chemistry 1994 Sep 23;269(38):23764-8
  15. Liu L, Damen JE, Ware MD, Krystal G
    Interleukin-3 induces the association of the inositol 5-phosphatase SHIP with SHP2. The Journal of biological chemistry 1997 Apr 25;272(17):10998-1001
  16. Sattler M, Salgia R, Shrikhande G, Verma S, Choi JL, Rohrschneider LR, Griffin JD
    The phosphatidylinositol polyphosphate 5-phosphatase SHIP and the protein tyrosine phosphatase SHP-2 form a complex in hematopoietic cells which can be regulated by BCR/ABL and growth factors. Oncogene 1997 Nov 6;15(19):2379-84
  17. Yu WM, Hawley TS, Hawley RG, Qu CK
    Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling. Oncogene 2003 Sep 4;22(38):5995-6004
  18. Koyano-Nakagawa N, Nishida J, Baldwin D, Arai K, Yokota T
    Molecular cloning of a novel human cDNA encoding a zinc finger protein that binds to the interleukin-3 promoter. Molecular and cellular biology 1994 Aug;14(8):5099-107
  19. Gottschalk LR, Giannola DM, Emerson SG
    Molecular regulation of the human IL-3 gene: inducible T cell-restricted expression requires intact AP-1 and Elf-1 nuclear protein binding sites. The Journal of experimental medicine 1993 Nov 1;178(5):1681-92
  20. Duncliffe KN, Bert AG, Vadas MA, Cockerill PN
    A T cell-specific enhancer in the interleukin-3 locus is activated cooperatively by Oct and NFAT elements within a DNase I-hypersensitive site. Immunity 1997 Feb;6(2):175-85
  21. Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A
    Transcriptional mechanisms underlying lymphocyte tolerance. Cell 2002 Jun 14;109(6):719-31