Mechanistic diversity of cytokine receptor signaling across cell membranes.

Circulating cytokines bind to specific receptors on the cell outer surface to evoke responses inside the cell. Binding of cytokines alters the association between receptor molecules that often cross the membrane only once in a single alpha-helical segment. As a consequence, association of protein domains on the inside of the membrane are also altered. Increasing evidence suggests that an initial "off-state" of associated receptors is perturbed, and brought to an activated state that leads to intracellular signaling and eventually effects a change in DNA transcription. The initial detection event that transduces the change in receptor association is sensitive to both proximity and orientation of the receptors, and probably also to the time that the activated state or receptor association is maintained. Ultimately, a cascade of phosphorylation events is triggered. The initial kinases are sometimes part of the intracellular domains of the receptors. The kinases can also be separate proteins that may be pre-associated with intracellular domains of the receptors, or can be recruited after the intracellular association of the activated receptors. We focus here on each of the cases for which structures of the activated cytokine-receptor complexes are known, in a search for underlying mechanisms. The variations in modes of association, stoichiometries of receptors and cytokines, and orientations before and after activation of these receptors are almost as great as the number of complexes themselves. The principles uncovered nevertheless illustrate the basis for high specificity and fidelity in cytokine-mediated signaling.