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The structure-function relationship of oncogenic LMTK3

DOI: 10.1126/sciadv.abc3099 DOI Help

Authors: Angeliki Ditsiou (University of Sussex) , Chiara Cilibrasi (University of Sussex) , Nikiana Simigdala (Biomedical Research Foundation of the Academy of Athens) , Athanasios Papakyriakou (National Centre for Scientific Research) , Leanne Milton-harris (University of Sussex) , Viviana Vella (University of Sussex) , Joanne E. Nettleship (The Wellcome Centre for Human Genetics, University of Oxford; Research Complex at Harwell;) , Jae Ho Lo (University of Southern California) , Shivani Soni (University of Southern California) , Goar Smbatyan (University of Southern California) , Panagiota Ntavelou (Biomedical Research Foundation of the Academy of Athens) , Teresa Gagliano (University of Sussex) , Maria Chiara Iachini (University of Sussex) , Sahir Khurshid (Imperial College London) , Thomas Simon (University of Sussex) , Lihong Zhou (University of Sussex) , Storm Hassell-hart (University of Sussex) , Philip Carter (mperial College London) , Laurence H. Pearl (University of Sussex) , Robin L. Owen (Diamond Light Source) , Raymond J. Owens (The Wellcome Centre for Human Genetics, University of Oxford; Research Complex at Harwell; The Rosalind Franklin Institute) , S. Mark Roe (University of Sussex) , Naomi E. Chayen (Imperial College London) , Heinz-josef Lenz (University of Southern California) , John Spencer (University of Sussex) , Chrisostomos Prodromou (University of Sussex) , Apostolos Klinakis (Biomedical Research Foundation of the Academy of Athens) , Justin Stebbing (Imperial College London) , Georgios Giamas (University of Sussex)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 6

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 14493

Open Access Open Access

Abstract: Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled with biochemical, cellular, and biophysical assays, we identify a potent LMTK3 small-molecule inhibitor (C28). Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3. Pharmacologic inhibition of LMTK3 decreases proliferation of cancer cell lines in the NCI-60 panel, with a concomitant increase in apoptosis in breast cancer cells, recapitulating effects of LMTK3 gene silencing. Furthermore, LMTK3 inhibition reduces growth of xenograft and transgenic breast cancer mouse models without displaying systemic toxicity at effective doses. Our data reinforce LMTK3 as a druggable target for cancer therapy.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography