Oral Presentation 2019 Hunter Cell Biology Meeting

Mechanisms of dysregulated cytokine receptor signalling in cancer (#25)

Livia Weijenborg Campos 1 2 , Christine Lee 1 , Farhad Dehkhoda 1 , Yash Chhabra 1 , Robert Luetterforst 1 , Raphael Trenker 3 , Rachel Gormal 4 , Katrine Bugge 5 , Kathryn A Tunny 1 , Nela A Durisic 4 , Birthe B Kragelund 5 , Michael J Waters 6 , Matthew E Call 3 , Melissa J Call 3 , José A Yunes 2 , Frederic A Meunier 4 , Andrew J Brooks 1
  1. The University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
  2. Centro Infantil Boldrini, Campinas, SP, Brazil
  3. Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  4. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
  5. Department of Biology, University of Copenhagen, Copenhagen, Denmark
  6. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia

Cytokine receptor signalling regulates a diverse range of cellular and physiological properties including cell proliferation, differentiation, inflammation, metabolism, and growth. The major signalling pathway regulated by cytokine receptors is the JAK-STAT pathway and dysregulation of this signalling is common in cancer, particularly in haematological cancers. Our previous studies centred on understanding how cytokine binding transmitted a signal through the transmembrane domain to the associated JAK kinases. These studies highlighted the critical structural nature of the transmembrane and juxtamembrane regions of cytokine receptors. Mutations in the interleukin-7 receptor alpha chain (IL-7Ra), thymic stromal lymphopoietin protein receptor (TSLPR), and thrombopoietin receptor (TPOR/MPL) are common in the transmembrane and juxtamembrane region in leukaemia and myeloproliferative neoplasms. We have recently defined the mechanism of how mutations in the IL-7Ra that introduce positive charged amino acids at the extracellular transmembrane boundary contribute to enhanced JAK-STAT signalling and T-cell leukaemia. We have also investigated the mechanism of different clinical activating mutants in the transmembrane domain of TPOR and find differential strengths of STAT and Erk1/2 signalling. Negative regulation of JAK signalling is also an important feature regulating cytokine receptor signalling with mutations in LNK (a negative regulator of JAK2) also identified in proliferative haematological disorders. We have investigated the molecular interactions of LNK with JAK2 and TPOR and their role in regulating signalling. In addition, we have studied cytokine receptor oligomerisation and membrane dynamics at the single molecule level using single-step photobleaching and live-cell single-particle tracking with photoactivated localization microscopy (spt-PALM), as this new knowledge is critical for our understanding of the mechanism of receptor activation and regulation at the cell membrane. Our studies will provide novel insights into cytokine receptor activation and signalling, and an increased understanding of diseases caused by dysregulated JAK-STAT signalling.