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Immune response IL-3 activation and signaling pathway


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Immune response IL-3 activation and signaling pathway

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-potentialhematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoidand 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 associatedonly in the presence of ligand [2], [1].

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

Activated JAK2 phosphorylates STAT5. The latter dimerizes, translocatesto the nucleus and activates transcription of genes, including Cytokine inducibleSH2-containing protein ( CISH ), Oncostatin M, Inhibitor of DNA binding 1dominant 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 withSuppressors of cytokine signaling 1 and 3 ( SOCS1 and SOCS3 ) andpotentiates their inhibitory effects on JAK2/ STAT5 signaling, most likelyvia phosphorylation-mediated stabilization of SOCS1 and SOCS3 proteins[10].

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

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

Upon IL-3 stimulation, the adaptor molecule Shc is rapidlyphosphorylated and associates with the phosphorylated IL-3 receptor. IL-3stimulation also results in the activation of SHIP which associates withShc and GRB2 that form a complex with Son of sevenless homologs (SOS ), followed by the activation of v-Ha-ras Harvey rat sarcoma viral oncogenehomolog ( H-Ras ), v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1 ), Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 andMEK2 ), ERK1/2 and ELK1 member of ETS oncogene family ( Elk-1 ).Activation of this cascade culminates in the increased expression of transcriptionfactors, 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 cellreceptor signaling pathways. The T cell-specific expression of the IL-3 gene iscontrolled 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].