Our lab seeks to understand how the protein kinase family organises complex intracellular communication networks. We are particularly interested in acquiring a deep understanding at the molecular level of the catalysis-independent signalling functions of kinase/pseudokinase scaffold.
We employ a multidisciplinary approach including kinase biochemistry and biology, structural biology (X-ray crystallography and cryo-electron microscopy), assay development, high-throughput screening, proteomics, imaging and chemical biology to gain high-resolution insights into kinase/pseudokinase signaling proteins.
France, University of Angers, PhD
France, University of Nantes, BSc (Hons)
2003-2009 Industry Research Fellow, (Monash University/ Cytopia PTY Ltd) National Health and Medical Research Council
2023, Ideas Grant, NHMRC, Elucidating the signalling functions of Transmembrane Pseudokinases as a strategy to develop novel therapeutics modalities
2021, Investigator Grant, NHMRC, Harnessing cryo-electron microscopy to study the engineering of microtubule networks in cancer and neurogenesis
2020, ARC Linkage Program, Industrial Transformation Training Centres (ITTC)
2019, Project Grant, NHMRC, Structural and functional characterisation of the microtubule-binding protein DCLK1
2018, Project Grant, NHMRC, Assembly and function of two interacting oncogenic scaffolds
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 Mar 22;11(3):990. doi: 10.3390/biomedicines11030990.
Patel O, Surudoi M, Dai W, Hardy J, Roy MJ, Lucet IS. Production and purification of the PEAK pseudokinases for structural and functional studies. Methods Enzymol. 2022;667:1-35. doi: 10.1016/bs.mie.2022.03.022.
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 Crystallography D Struct Biol. (2022) Apr 1;78(Pt 4):494-508.
Hou J, Nguyen EV, Surudoi M, Roy MJ, Patel O, Lucet IS, Ma X, Daly RJ. Distinct PEAK3 interactors and outputs expand the signaling potential of the PEAK pseudokinase family. Sci Signal. 2022 Feb 22;15(722):eabj3554.
Patel O, Roy MJ, Kropp A, Hardy JM, Dai W, Lucet IS. Structural basis for small molecule targeting of Doublecortin like kinase 1 with DCLK1-IN-1. Commun Biol 2021 4(1):1105. DOI: 10.1038/s42003-021-02631-y PMID: 34545159
Liang LY, Roy M, Horne CR, Sandow JJ, Surudoi M, Dagley LF, Young SN, Dite T, Babon JJ, Janes PW, Patel O, Murphy JM, Lucet IS. The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs. Biochem J. 2021 Sep 17;478(17):3351-3371. doi: 10.1042/BCJ20210572. PMID: 34431498
Patel O, Roy MJ, Murphy JM, Lucet IS. The PEAK family of pseudokinases, their role in cell signalling and cancer. FEBS J. 2020 Oct;287(19):4183-4197. doi: 10.1111/febs.15087. PMID: 31599110
Liang LY, Patel O, Janes PW, Murphy JM, Lucet IS. Eph receptor signalling: from catalytic to non-catalytic functions. Oncogene. 2019 Sep;38(39):6567-6584. doi: 10.1038/s41388-019-0931-2. PMID: 31406248
Roy MJ, Winkler S, Hughes SJ, Whitworth C, Galant M, Farnaby W, Rumpel K and Ciulli A. SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate. ACS Chem Biol. 2019 Mar 15;14(3):361-368. PMID: 30721025.
Patel O, Griffin MDW, Panjikar S, Dai W, Ma X, Chan H, Zheng C, Kropp A, Murphy JM, Daly RJ, Lucet IS. Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association. Nature Communications, 2017 Oct 27;8(1):1157. doi: 10.1038/s41467-017-01279-9. PMID: 29079850
Patel O, Dai W, Mentzel M, Griffin MD, Serindoux J, Gay Y, Fischer S, Sterle S, Kropp A, Burns CJ, Ernst M, Buchert M, Lucet IS. Biochemical and Structural Insights into Doublecortin-like Kinase Domain 1. Structure. 2016 Sep 6;24(9):1550-61. doi: 10.1016/j.str.2016.07.008. PMID: 27545623
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.
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.
News, 19 Aug 2016: First 3D map of cell-building protein linked to cancer
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.
News, 27th October 2017: 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).
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.