The mechanism of GM-CSF receptor activation

The human GM-CSF receptor is a heterodimer composed of a ligand-specific a chain and a βchain (βc) which is shared by the receptors for IL-3 and IL-5. Structurally and functionally the receptor for GM-CSF is closely related to the IL-3 and IL-5 receptors. We have found that functionally these receptors utilize the same regions in βc for binding with high affinity, and a conserved Cys motif in the N-terminus of βc is required for GM-CSF, IL-3 and IL-5 receptor activation. As well as these common mechanisms, we have now found that the human GMCSF receptor exhibits some unique properties. Using biochemical and binding kinetics approaches, we have found that the human GM-CSF receptor exists in two pools, one representing an inducible receptor analogous to the IL-3 and IL5 receptors, and a second one representing a novel preformed complex. Interestingly, whilst stimulation of cells with GM-CSF leads to only activation of the GM-CSF receptor, stimulation with IL-3 and IL-5 causes activation of the cognate receptor as well as activation of the GM-CSF receptor. We hypothesize that transactivation of the GM-CSF receptor by IL-3 and IL-5 is mediated by the preformed GM-CSF receptor complex and that this phenomenon has important implications for understanding hemopoiesis.