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
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 .
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 , , , .