Boster Pathways-> Cytokines

IL-3 Signaling Pathway

IL-3 is a cytokine that regulates haemopoiesis, the formation of blood cells in the body

Overview of IL-3 Pathway

IL-3 (Interleukin-3) is a cytokine that plays a role in haemopoiesis, the process by which blood cells are formed in the body. After activation with mitogens or antigens, T cells and mast cells produce IL-3, also known as multi-CSF (multi-lineage colony stimulating factor). The molecular weight of IL-3, a 140-amino acid protein, ranges between 14 and 36 kDa. It promotes the differentiation of eosinophils and B cells while inhibiting the activity of LAK (Lymphokine-Activated Killer) cells. IL-3 and GM-CSF share a number of biological activities. IL-3 has been shown to promote the growth and differentiation of multipotent haematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid, and erythroid cells. The IL-3R (IL-3 receptor) is composed of two polypeptide chains: an Alpha subunit with a molecular weight of 60-70kDa and a Beta subunit with a molecular weight of 130-140kDa. Both subunits contain extracellularly conserved motifs found in the superfamily of cytokine receptors.

The common Beta -chain receptor subunit (c), which is shared by the receptors for interleukin-3, interleukin-5, and granulocyte/macrophage colony-stimulating factor, is required for signal transduction during cell proliferation and differentiation induced by these cytokines, and is involved in the recruitment of intracellular signaling molecules such as JAK2 (Janus Kinase2) tyrosine kinase and STAT5 (Signal Transducers And Activators Of Transcription)

IL-3 Signaling Cascade

In the absence of ligand, the IL-3 receptor's Alpha and Betac chains are dissociated. The presence of ligand induces the association of alpha and beta chains, resulting in the formation of a heterodimeric complex. Following receptor activation, the receptor-associated JAK2 kinase is activated, as well as the cytoplasmic tail of the Betac chain is phosphorylated on tyrosine and serine. When JAK2 is activated, it phosphorylates the IL-3R Betac chain on multiple tyrosine residues, which act as docking sites for additional signal transducing proteins, the most important of which are STATs. When hematopoietic cells are activated with IL-3, multiple STATs appear to be activated, including STAT1, STAT3, STAT5, and STAT6. Additionally, IL-3 stimulation alters the morphology of cells via tyrosine phosphorylation of Betac and its associated protein pp90. Ectopically expressed RON tyrosine kinase associates with the IL-3 receptor Betac in unstimulated cells.

Src family kinases are responsible for the phosphorylation of STAT3 induced by IL-3/receptor interactions and are involved in signal transduction pathways involved in myeloid cell proliferation. While one or both STAT5 isoforms interact directly with JAK2, which mediates their phosphorylation, activation of STAT3 requires its interaction with c-Src, which mediates its phosphorylation. Apart from activating STATs, IL-3 activates a variety of signaling pathways, including the Ras and PI3K (Phosphatidylinositol-3 Kinase) pathways. When stimulated with IL-3, the adapter molecule SHC (Src Homology 2 Domain Containing) transforms into a phosphorylated transforming protein that associates with the phosphorylated Betac subunit of IL-3. Additionally, IL-3 stimulates the inositol phosphatase SHIP (SH2-Containing Inositol Phosphatase), which forms a complex with SHC, GRB2 (Growth Factor Receptor-Bound Protein 2), and SOS (Son Of Sevenless). This is followed by Ras and c-Raf activation, which results in the activation of ERK1 and ERK2 downstream (Extracellular Signal-Regulated Kinases). Cascade activation results in an increase in the expression of the transcription factors c-Jun and c-Fos.

Along with ERKs, IL-3 activates p38 and JNK. IL-3 rapidly activates the lipid kinase PI3K. The Akt protein is one of the downstream proteins recruited by the PI3K pathways in response to IL-3 stimulation. Another downstream protein activated by IL-3 is p70S6k (p70 Ribosomal S6 Kinase), which also exerts its effect via interaction with the Betac chain. The Cbl protein, which also docks onto the adaptor proteins GRB2 and SHC, is another protein that contributes to the PI3K-PKB/AKT pathway. The BCL2 family is involved in IL-3's cell survival function. BCL2 and BCLXL are rapidly induced by IL-3, a factor that requires activation of JAK2. Additionally, IL-3 acts as a regulator of the glycolytic pathway. In Baf-3 cells, IL-3 deficiency reduces glucose uptake and lactate production. It is discovered that eosinophils activated by IL-3 may aid in the activation of T cells in allergic and parasitic diseases by presenting superantigens and peptides to T cells.