The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities

ABSTRACT Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), interleukin (IL)‐3, and IL‐5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an “all or none” phenomenon. Subtle alterations of the cytokine:receptor complex can result in differential or selective signaling and underpin a variety of diseases including chronic inflammatory conditions and cancers. Structural biology techniques, such as X‐ray crystallography and cryo‐electron microscopy alongside cell biology studies, are providing detailed insights into cytokine receptor signaling. Recently, we found that the IL‐3 receptor ternary complex forms higher‐order assemblies, like those found earlier for the GM‐CSF receptor, and demonstrated that functionally distinct biological signals arise from different IL‐3 receptor oligomeric assemblies. As we enhance our understanding of the structural nuances of cytokine–receptor interactions, we foresee a new era of theranostics whereby structurally guided mechanism‐based manipulation of cytokine signaling through rational/targeted protein engineering will harness the full potential of cytokine biology for precision medicine.