The GM-CSF receptor: initiation of signal transduction. In the absence of GM-CSF, preformed βc dimers as well as single GM-CSFRα chains are present on the plasma membrane. Low affinity binding of GM-CSF to GM-CSFRα causes association with a βc dimer. This leads to the formation of a hexamer of 2 GM-CSF molecules, 2 GM-CSFRα chains, and 2 βc chains, and induces high-affinity GM-CSF/GM-CSFRα binding. Two of these hexamers then dimerize. This brings the βc subunits in close enough proximity to enable JAK2 transactivation, which initiates downstream signaling. Activated JAK2 phosphorylates several tyrosine domains on βc (Y577, Y612, Y695, Y750, Y806, and Y866), which subsequently serve as docking sites for a variety of proteins. Phosphorylation of recruited STATs results in their activation and serves as start of signaling. Activation of the MAPK pathway is initiated by recruitment of SHC to Y577. Its subsequent phosphorylation allows interaction with GRB2 and mSOS, after which the activation of RAS is catalyzed. Recruitment and activation of PI3K has also been suggested to depend on βc residue phosphorylation, and its activation is promoted by JAK2-mediated phosphorylation of PI3K. Finally, GM-CSF activates canonical NF-κB transcription factors. Activation of the IKK complex as a direct consequence of GM-CSFR engagement has been reported, but the proteins involved and the complete chain of events remain to be elucidated.^21,,,,–26