Overview of Common beta Chain Receptor Family
Granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin-3 (IL-3) and Interleukin-5 (IL-5) are related hematopoietic cytokines which play important roles on hematopoietic cells, including neutrophils, eosinophils, monocytes and early progenitor cells. A common β-subunit (βc) is shared by the high-affinity receptors for human GM-CSF, IL-3, and IL-5, which is indispensable for signaling and plays a major role in recruiting intracellular signaling molecules. These receptors are all heterodimers, comprised by a cytokine-specific α subunit and a common β-subunit mentioned above. The α subunit binds cytokines with low affinity, but βc has a high affinity to bind to cytokines by the receptor heterodimerization, which will activate multiple signaling pathways triggering a range of biological functions. The binding of cytokine to GM-CSF, IL-3, and IL-5 receptor causes the activation of receptor-asociated Janus kinases (JAKs), mainly JAK2, which is important for downstream signaling and receptor function, which will play a role in the cell survival, proliferation, and differentiation. JAK2 activation leads to transphosphorylarion of six critical tyrosine residues in βc. In these residues, phosphorylation of S585 is a docking site for other signaling molecules and activation of the JAK/signal transducer and activator of transcription (STAT), Ras-mitogen-associated protein kinase (MAPK), and phosphoinositol 3-kinase (PI3K) pathways.
Common beta Chain Receptor Family
GM-CSF is important for innate and adaptive immune responses to infections and some inflammatory diseases, for example, asthma, rheumatoid arthritis, autoimmune glomerulonephritis and multiple sclerosis. T cells, epithelial cells, as well as macrophages all produce GM-CSF in response to a number of inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α). GM-CSF is regarded as a growth factor and a survival factor for several myeloid leukemias. Interestingly, in acute myeloid leukemia (AML), βc is constitutively phosphorylated on S585. GM-CSF receptor activation via S585 will be beneficial for the leukemic clone survival.
IL-3 is a cytokine that produces and functions in the immune and hematopoietic systems. Up to now, considerable evidence has been accumulated that IL-3 and its receptor play a major role in several human pathologies, especially cancer and inflammation. From the mutagenesis studies of βc, Y39 and F103 of βc domain 1 and Y421 of βc domain 4 are very critical for the high binding affinity to IL-3. Unlike GM-CSF, the residues of Y365, H367, and I368 in IL-3 are not essential for the high-affinity of IL-3. Similar to GM-CSF, the IL-3 receptor complex is mostly likely to form a hexamer via three interaction surfaces, defined as sites 1-3. After forming the binary complex, the βc dimer is recruited to the complex through sites 2 and 3. These interfaces function together to stabilize the overall complex, resulting in the high-affinity of IL-3.
Unlike GM-CSF and IL-3, IL-5 is a cytokine which shows lineage restriction. The proliferation, maturation, and functional activation of eosinophils and basophils are all stimulated by IL-5. T cells are the major cellular source of IL-5. As we know, most cytokines, including GM-CSF and IL-3, exist as monomers. However, IL-5 is comprised of two left-handed four-helix bundles with two short β sheets on opposite sites of the molecule uniquely. IL-5’s two monomers are packed by an intimate dimerization interface which involves hydrophobic, electrostatic, and disulfide bonds which are very crucial for the structural integrity of IL-5
Relations with human diseases
Due to the pleiotropic biological activities of the GM-CSF / IL-3 / IL-5 receptor family, the issue of whether these receptors may interact with other cytokine receptors and other membrane proteins at the cell surface has been recurrently raised. As such interactions may have additional or unique biological activities, the character may be utilized to selectively modulate the function of these receptors in human diseases. There is a large body of biochemical evidence that the GM-CSF / IL-3 / IL-5 receptor family does interact effectively with other membrane proteins on the cell surface. GM–CSF/IL-3/IL-5 receptor assembly, signaling and the molecular basis of cytokine pleiotropy may provide some new therapeutic approaches for the management of diseases where these cytokines play a major pathogenic role.