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The structure-function relationship of oncogenic LMTK3
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 homogen...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673765/ https://www.ncbi.nlm.nih.gov/pubmed/33188023 http://dx.doi.org/10.1126/sciadv.abc3099 |
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author | Ditsiou, Angeliki Cilibrasi, Chiara Simigdala, Nikiana Papakyriakou, Athanasios Milton-Harris, Leanne Vella, Viviana Nettleship, Joanne E. Lo, Jae Ho Soni, Shivani Smbatyan, Goar Ntavelou, Panagiota Gagliano, Teresa Iachini, Maria Chiara Khurshid, Sahir Simon, Thomas Zhou, Lihong Hassell-Hart, Storm Carter, Philip Pearl, Laurence H. Owen, Robin L. Owens, Raymond J. Roe, S. Mark Chayen, Naomi E. Lenz, Heinz-Josef Spencer, John Prodromou, Chrisostomos Klinakis, Apostolos Stebbing, Justin Giamas, Georgios |
author_facet | Ditsiou, Angeliki Cilibrasi, Chiara Simigdala, Nikiana Papakyriakou, Athanasios Milton-Harris, Leanne Vella, Viviana Nettleship, Joanne E. Lo, Jae Ho Soni, Shivani Smbatyan, Goar Ntavelou, Panagiota Gagliano, Teresa Iachini, Maria Chiara Khurshid, Sahir Simon, Thomas Zhou, Lihong Hassell-Hart, Storm Carter, Philip Pearl, Laurence H. Owen, Robin L. Owens, Raymond J. Roe, S. Mark Chayen, Naomi E. Lenz, Heinz-Josef Spencer, John Prodromou, Chrisostomos Klinakis, Apostolos Stebbing, Justin Giamas, Georgios |
author_sort | Ditsiou, Angeliki |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7673765 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-76737652020-11-24 The structure-function relationship of oncogenic LMTK3 Ditsiou, Angeliki Cilibrasi, Chiara Simigdala, Nikiana Papakyriakou, Athanasios Milton-Harris, Leanne Vella, Viviana Nettleship, Joanne E. Lo, Jae Ho Soni, Shivani Smbatyan, Goar Ntavelou, Panagiota Gagliano, Teresa Iachini, Maria Chiara Khurshid, Sahir Simon, Thomas Zhou, Lihong Hassell-Hart, Storm Carter, Philip Pearl, Laurence H. Owen, Robin L. Owens, Raymond J. Roe, S. Mark Chayen, Naomi E. Lenz, Heinz-Josef Spencer, John Prodromou, Chrisostomos Klinakis, Apostolos Stebbing, Justin Giamas, Georgios Sci Adv Research Articles 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. American Association for the Advancement of Science 2020-11-13 /pmc/articles/PMC7673765/ /pubmed/33188023 http://dx.doi.org/10.1126/sciadv.abc3099 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Ditsiou, Angeliki Cilibrasi, Chiara Simigdala, Nikiana Papakyriakou, Athanasios Milton-Harris, Leanne Vella, Viviana Nettleship, Joanne E. Lo, Jae Ho Soni, Shivani Smbatyan, Goar Ntavelou, Panagiota Gagliano, Teresa Iachini, Maria Chiara Khurshid, Sahir Simon, Thomas Zhou, Lihong Hassell-Hart, Storm Carter, Philip Pearl, Laurence H. Owen, Robin L. Owens, Raymond J. Roe, S. Mark Chayen, Naomi E. Lenz, Heinz-Josef Spencer, John Prodromou, Chrisostomos Klinakis, Apostolos Stebbing, Justin Giamas, Georgios The structure-function relationship of oncogenic LMTK3 |
title | The structure-function relationship of oncogenic LMTK3 |
title_full | The structure-function relationship of oncogenic LMTK3 |
title_fullStr | The structure-function relationship of oncogenic LMTK3 |
title_full_unstemmed | The structure-function relationship of oncogenic LMTK3 |
title_short | The structure-function relationship of oncogenic LMTK3 |
title_sort | structure-function relationship of oncogenic lmtk3 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673765/ https://www.ncbi.nlm.nih.gov/pubmed/33188023 http://dx.doi.org/10.1126/sciadv.abc3099 |
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