Prof Isabelle Lucet, Lab Head | WEHI Researcher Profile

Q: Elucidating the signalling functions of Transmembrane Pseudokinases as a strategy to develop novel therapeutics modalities

Receptor tyrosine pseudokinases have emerged as critical players in developmental processes. Deregulation of this class of proteins can lead to proliferative diseases such as cancers. By integrating cutting-edge structural biology with advanced imaging technologies, innovative chemical biology and proteomics approaches, we aim to elucidate at the molecular level the structure and function of EphB6 and EphA10 and use this information to redefine EphR targetable space. This novel approach is built on years of expertise in the field of kinase drug discovery and leverages our work demonstrating that pseudokinases are druggable targets.

Q: Structural and functional characterisation of DCLK proteins: unravelling their role in cancer and neurogenesis

Overwhelming evidence associate DoubleCortin-Like Kinases (DCLK1, DCLK2, DCLK3) with several diseases, including neurodegenerative disorders and many cancers. Over the past few years, our laboratory has led the structural and functional characterisation of these understudied kinases and provided the structural basis for DCLK1 targeting by small molecules. Additionally, we elucidated how DCLK1 activity contributes to microtubule dynamics. Drawing on our expertise in kinase signalling and drug discovery, we aim to further our studies by combining advanced biochemical, biophysical, structural biology, chemical biology approaches with cutting-edge imaging technologies to develop novel class of compounds that specifically target DCLK proteins for therapeutic purposes.https://www.wehi.edu.au/news/first-3d-map-cell-building-protein-linked-cancer (News 19 Aug 2016, Title: First 3D map of cell-building protein linked to cancerVideo: Art of Science finalist: Protein cave by Onisha Patel and Isabelle Lucet (https://youtu.be/NWY17wEy_Mo)

Q: Structural and functional characterisation of a new family of oncogenic signalling scaffolds

Members of the PEAK family of pseudokinases (PEAK1/2/3) have emerged as critical regulators of cell migration, invasion and proliferation. Several studies have demonstrated abnormal levels of PEAK proteins in aggressive cancers. Recently, we have uncovered the unique structural elements that drive their scaffolding functions and facilitate their dynamic assembly into a protein interaction hub that regulates signalling networks. We now aim to fully characterise the signal integrating function of each member of the PEAK family and provide near-atomic resolution of the interacting interfaces that contribute to abnormal signal output in cancer.https://www.wehi.edu.au/news/3d-scaffold-map-help-search-new-cancer-treatments (News: 27th October 2017, Title: 3D 'scaffold' map to help the search for new cancer treatments)Project in collaboration with Associate Professor Kelly Rogers (Imaging facility, WEHI), Professor Roger Daly (Biomedical Discovery Institute, Monash University).

Q: Development of small molecule Targeted Protein Degraders / PROTACs

Together with the lab of Professor John Silke and a leading global pharmaceutical company, we head an academic/industry research collaboration to discover and develop novel small molecule Targeted Protein Degraders / Proteolysis Targeting Chimaeras (PROTACs), that harness the degradative capacity of Ubiquitin E3 ligases for anti-cancer therapy.

About

As a leading expert in kinase structural biology and drug discovery, my lab investigates the complex intracellular communication networks orchestrated by the protein kinase family, with a particular focus on the non-catalytic signalling functions of kinase and pseudokinase scaffolds.

We employ a multidisciplinary approach, combining kinase biochemistry, structural biology, high-throughput screening, proteomics, advanced imaging, chemical biology, and de novo protein design to gain high-resolution insights into these signalling proteins.

Our aim is to unravel deregulation mechanisms, develop innovative targeting strategies, and translate key signalling signatures into novel diagnostics and therapies for aggressive cancers, inflammatory conditions, and neurological disorders.

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Selected publications from Prof Isabelle Lucet

Roy MJ, Surudoi MG, Kropp A, Hou J, Dai W, Hardy JM, Liang L-Y, Cotton TR, Lechtenberg BC, Dite TA, Ma X, Daly RJ, Patel O, Lucet IS. Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling. Nature Communications. 2023;14(1):10.1038/s41467-023-38869-9

Lucet IS, Daly RJ. View from the PEAKs: Insights from structural studies on the PEAK family of pseudokinases. Current Opinion in Structural Biology. 2024;89:10.1016/j.sbi.2024.102932

Afshar-Sterle S, Carli ALE, O’Keefe R, Tse J, Fischer S, Azimpour AI, Baloyan D, Elias L, Thilakasiri P, Patel O, Ferguson FM, Eissmann MF, Chand AL, Gray NS, Busuttil R, Boussioutas A, Lucet IS, Ernst M, Buchert M. DCLK1 induces a pro-tumorigenic phenotype to drive gastric cancer progression. Science Signaling. 2024;17(854):10.1126/scisignal.abq4888

Diplock N, Baudin M, Xiang X, Liang L-Y, Dai W, Murphy JM, Lucet IS, Hassan JA, Lewis JD. Molecular dissection of the pseudokinase ZED1 expands effector recognition to the tomato immune receptor ZAR1. Plant Physiology. 2024;196(1):10.1093/plphys/kiae268

Liang L-Y, Geoghegan ND, Mlodzianoski M, Leis A, Whitehead LW, Surudoi MG, Young SN, Janes P, Shepherd D, Ghosal D, Rogers KL, Murphy JM, Lucet IS. Co-clustering of EphB6 and ephrinB1 in trans restrains cancer cell invasion. Communications Biology. 2024;7(1):10.1038/s42003-024-06118-4

Roy MJ, Surudoi M, Kropp A, Hou J, Dai W, Hardy JM, Liang L-Y, Cotton TR, Lechtenberg BC, Dite TA, Ma X, Daly RJ, Patel O, Lucet IS. Structural mapping of the PEAK pseudokinase interactome identifies 14-3-3 as a molecular switch regulating PEAK3/Crk signalling. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323086850

Horne CR, Oliver MR, Shrestha S, Keown JR, Liang L-Y, Young SN, Sandow JJ, Webb AI, Goldstone DC, Lucet IS, Kannan N, Metcalf P, Murphy JM. It takes two to tango: structure of viral kinase PK-1 reveals a new mode of kinase regulation. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323087715

Ameen SS, Griem-Krey N, Dufour A, Hossain MI, Hoque A, Sturgeon S, Nandurkar H, Draxler DF, Medcalf RL, Kamaruddin MA, Lucet IS, Leeming MG, Liu D, Dhillon A, Lim JP, Basheer F, Zhu H-J, Bokhari L, Roulston CL, Paradkar PN, Kleifeld O, Clarkson AN, Wellendorph P, Ciccotosto GD, Williamson NA, Ang C-S, Cheng H-C. N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection. Molecular & Cellular Proteomics. 2023;22(5):10.1016/j.mcpro.2023.100543

Carli ALE, Hardy JM, Hoblos H, Ernst M, Lucet IS, Buchert M. Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis. Biomedicines. 2023;11(3):10.3390/biomedicines11030990

Patel O, Brammananth R, Dai W, Panjikar S, Coppel RL, Lucet IS, Crellin PK. Crystal structure of the putative cell-wall lipoglycan biosynthesis protein LmcA from Mycobacterium smegmatis. Acta Crystallographica Section D, Structural Biology. 2022;78(Pt 4):10.1107/s2059798322001772

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Lab research projects

Elucidating the signalling functions of Transmembrane Pseudokinases as a strategy to develop novel therapeutics modalities

Structural and functional characterisation of DCLK proteins: unravelling their role in cancer and neurogenesis

Structural and functional characterisation of a new family of oncogenic signalling scaffolds

Development of small molecule Targeted Protein Degraders / PROTACs

Prof Isabelle Lucet

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