Understanding biological signalling in the βc cytokine receptor family

Abstract

The beta-common ( βc) family of cytokines, namely granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5, are modulators of cell survival, differentiation and proliferation during normal and malignant haematopoiesis. They have recently been shown to act outside the haematopoietic system, playing roles in the nervous system. Aberrant signalling from the bc cytokines has been linked to many diseases, such as leukaemia and asthma. These cytokines signal by binding to heteroreceptors made of a cytokine specific a-subunit and the b-subunit, which interacts with all three cytokines (bc subunit). As such, the shared use of the bc subunit by GM- CSF, IL-3 and IL-5 makes it an attractive target of investigation for novel therapeutics that would disrupt the interaction of all three cytokines with their receptors. The studies undertaken have focussed on investigating the assembly mechanism of the bc receptor complexes, as well as identifying small molecule inhibitors and monoclonal antibodies targeting the interaction interfaces formed within the signalling complex. These inhibitors will aid in understanding the downstream signalling pathways activated by the βc family of cytokines and may elucidate new targets for drug discovery. Investigating the interaction between the βc subunit and putative binding partners such as the erythropoietin receptor (EPOR), janus kinase 2 (JAK2) and the 14-3-3 family has also been part of these studies. The βc subunit and EPOR have been reported to form an innate repair receptor complex under stress and I have demonstrated that the extracellular regions of the two receptors are not sufficient to mediate a direct interaction. The first steps towards understanding how two main intracellular pathways activated by the βc cytokines, the JAK-STAT and the PI3K pathways, are triggered 2 through the interaction of the βc subunit with JAK2 and the 14-3-3 family have also been undertaken. Throughout my PhD studies, I have utilised a wide array of biophysical techniques and crystallisation methods. The outcomes of this research will expand the understanding of the signalling of the family of βc cytokines, opening new avenues for the development of therapeutics.