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 .
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 , .
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) , , , .
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) , , , . 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 .
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 , , .
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
, , , .
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) .
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 , , , .
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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