Interleukin 3 (IL-3) is a potent growth factor belonging to the super family of cytokines. IL-3 is a 20- 32kDa glycoprotein involved in the process of hematopoiesis. It is involved in the proliferation and differentiation of pleuripotent hematopoietic stem cells, progenitor cells and their mature progeny (1,2,3). IL-3 is a growth factor for B lymphocytes (4,5). It also activates monocytes (6) and augments survival and propagation of mast cells (7), eosinophils (8) and stromal cells (9). IL-3 is secreted predominantly by activated T lymphocytes in response to immunological stimuli and to a lesser extent by mast cells and eosinophils. IL-3 exerts influence on different biological activities, primarily hematopoiesis by associating with the IL-3 receptor. This receptor is a heterodimeric complex and consists of an alpha chain- IL3RA and a beta chain CSF2RB, shared with the receptors for granulocyte macrophage colony stimulating factor and Interleukin-5 (1,2 10, 11,12).

When IL-3 binds to CSF2RB receptor, adapter proteins like SHC1 (13, 14), GRB2 (15, 16) and SOS1 (17, 18) are recruited to activate HRAS (18). HRAS stimulates RAF1 (18) which further activates MAP2K1 (20) and finally MAPK1 and MAPK3 (18). The signals generated through this pathway are then transmitted to the nucleus leading to the activation of various transcription factors such as JUN and FOS which are involved in the regulation of cell growth and differentiation (18, 21). IL-3 mediated activation of HRAS also inhibits apoptosis through phosphatidyl inositol 3 kinase/ AKT pathway. (22) The activation of AKT1 (18,23) in response to IL-3 stimulation leads to the phosphorylation of the apoptotic regulator, BCL2-associated agonist of cell death (BAD) (24,25,26,27), its binding to 14-3-3 and sequestration into the cytoplasm (23). IL-3 stimulation activates Janus kinase 2 (JAK2) (28) by its phosphorylation. JAK2 in turn phosphorylates signal transducer and activator of transcription 5A and 5B (29,30). These translocate to the nucleus, serving the purpose of transcription factor for early genes as well as a feedback inhibitor of the JAK-STAT pathway (31). IL-3, in addition, is known to activate various tyrosine kinases such as LYN, FYN, SRC, SYK, TEC1 and HCK (32,33,34). The interactions and intersections between canonical and noncanonical IL-3 signaling systems are depicted in the pathway map.

References

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