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The structure-function relationship of oncogenic LMTK3

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posted on 2023-06-09, 22:11 authored by Angeliki Ditsiou, Chiara Cilibrasi, Nikiana Simigdala, Leanne Harris, Viviana Vella, Teresa Gagliano, Maria Chiara Iachini, Thomas Simon, Lihong Zhou, Storm Hassell-HartStorm Hassell-Hart, Laurence PearlLaurence Pearl, S Mark Roe, John SpencerJohn Spencer, Chrisostomos ProdromouChrisostomos Prodromou, Georgios GiamasGeorgios Giamas, others
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

Funding

Synthesis and screening of compounds to be used as LMTK3 inhibitors; G1828; ACTION AGAINST CANCER; 112015-01

Identification of LMTK3 substrates (In vitro & in vivo) and further optimisation of LMTK3 inhibitors; G1731; ACTION AGAINST CANCER; 102015-03

History

Publication status

  • Published

File Version

  • Published version

Journal

Science Advances

ISSN

2375-2548

Publisher

American Association for the Advancement of Science

Issue

46

Volume

6

Page range

1-19

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2020-11-16

First Open Access (FOA) Date

2020-11-16

First Compliant Deposit (FCD) Date

2020-11-15

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