Poster Presentation 25th Lorne Cancer Conference 2013

The partially-assembled GM-CSF receptor hexameric complex mediates cell survival (#225)

Winnie LT Kan 1 , Emma F Barry 1 , Frank C Stomski 1 , Barbara J McClure 1 , Mara Dottore 1 , Timothy R Hercus 1 , Michael W Parker 2 3 , Angel F Lopez 1
  1. Division of Human Immunology, Centre for Cancer Biology, Adelaide, SA, Australia
  2. Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, Melbourne, Victoria, Australia
  3. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science Institute, The University of Melbourne, Melbourne, Victoria, Australia

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.

  1. 1. Hansen G et al. (2008). The structure of the GM-CSF receptor complex reveals a distinct mode of receptor activation. Cell 134, 496-507)
  2. 2. Hercus TR et al. (2009). The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood 114, 1289-1298.