15:20 - 16:50
Workshop 2, “Allergic disease”
Room: ANA Crowne Plaza “Ohtori” Room A
Workshop Session
Chair/s:
David Vöhringer, Hiroshi Nakajima
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The 3D structure of the human IL-3 receptor complex and a novel mode of cytokine signalling
Angel F Lopez1, Denis Tvovrogov1, Winne Kan1, Tim Hercus1, Sophie Broughton2, Urmi Dhagat2, Tracy Nero2, Karen S CheungTungShin2, Jeff Babon3, Jarrod Sandow3, David Ross4, Tim Hughes4, Michael Parker2
1The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia, 2ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Australia, 3The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, 4SAHMRI and SA Pathology, Adelaide, Australia

The human IL-3 receptor is a classic Type I cytokine receptor that signals in normal and malignant haemopoiesis. Composed of a specific alpha chain and a beta subunit which it shares with the GM-CSF and IL-5 receptors, the IL-3 receptor dimerises in the presence of IL-3 at the cell surface and triggers JAK-2 activation and other intracellular biochemical and signalling events which, once integrated, result in the stimulation of many cellular functions such as haemopoietic cell proliferation and differentiation1.

We and others have found that the IL-3 receptor signalling complex is dysregulated in malignant haemopoiesis. For example, the IL-3 receptor alpha chain (CD123) is overexpressed in acute myeloid leukaemia2 and chronic myeloid leukaemia progenitor cells3 providing a biological advantage4 whilst at the same time presenting a therapeutic opportunity to selectively target the leukaemic clones with monoclonal antibodies to CD123 such as CSL3625 and others. Similarly with JAK-2 , a kinase that is physically associated with the IL-3 receptor beta chain6. The JAK-2 mutant V617F is constitutively active and accounts for some of the abnormalities described in myeloproliferative disorders, although the molecular events linking this mutation to biological outcomes remain to be elucidated.

We have now molecularly characterised human IL-3 receptor signalling by a combination of X-ray crystallography, proteomics, and a functional approach that selectively targets JAK-1 and JAK-2. Evidence will be presented that the full extracellular ternary IL-3 receptor complex assembles as a dodecamer, analogous, yet distinct, from the GM-CSF receptor dodecamer complex. Furthermore, intermediate forms of receptor assembly are observed that recruit a distinct set of the full IL-3 receptor signalling machinery. Finally, a sequential model of receptor activation emerges which reveals the mode of action of JAK-1 and JAK-2 in this signalling complex. These results have profound implications for the design and clinical management of human hematopoietic malignancies.

Reference:
Mo-WS2-5
Session:
Workshop 2, “Allergic disease”
Presenter/s:
Angel F Lopez
Presentation type:
Oral Presentation
Room:
ANA Crowne Plaza “Ohtori” Room A
Chair/s:
David Vöhringer, Hiroshi Nakajima
Date:
Monday, 30 October 2017
Time:
16:10 - 16:20
Session times:
15:20 - 16:50
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