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 [1], [2].
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) [1], [3], [4], [5].
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].
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IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled.
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Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis.
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Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction.
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Physical and functional interactions between Stat5 and the tyrosine-phosphorylated receptors for erythropoietin and interleukin-3.
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Shc associates with the IL-3 receptor beta subunit, SHIP and Gab2 following IL-3 stimulation. Contribution of Shc PTB and SH2 domains.
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