Granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 are responsible for the survival, proliferation, differentiation and activation of hematopoietic cells and play a pathogenic role in leukemia and inflammatory diseases. GM-CSF signals through a receptor consisting of a ligand-specific α subunit and a β subunit (βc), which is shared with the interleukin-3 and interleukin-5 receptors. Our previous studies demonstrated that the GM-CSF receptor assembles into a hexamer consisting of 2 GM-CSF molecules, 2 α-chains and a βc homodimer and forms a higher-order dodecamer complex that is required for Jak2 transphosphorylation and full activation 1, 2. Disrupting dodecamer assembly through mutation of a specific motif in the βc subunit (Site 4) prevented full activation in response to GM-CSF but is still able to form a hexamer complex, as demonstrated by the high-affinity binding of GM-CSF, raising the question of its functional significance.
The aim of the present study was to functionally characterize signaling by the hexamer-only form of the GM-CSF receptor complex. GM-CSF stimulated cell survival in a dose- and time-dependent manner. Furthermore, AKT activation was seen by western blotting with phospho-AKT-specific antibodies. Current experiments are seeking to fully characterize this pathway and the potential of PI 3-kinase in mediating GM-CSF receptor hexamer function.