The Structure-function Relationship of Oncogenic LMTK3

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2020 Nov 14

PMID 33188023

Citations 22

Authors

Angeliki Ditsiou

Chiara Cilibrasi

Nikiana Simigdala

Athanasios Papakyriakou

Leanne Milton-Harris

Viviana Vella

Joanne E Nettleship

Jae Ho Lo

Shivani Soni

Goar Smbatyan

Panagiota Ntavelou

Teresa Gagliano

Maria Chiara Iachini

Sahir Khurshid

Thomas Simon

Lihong Zhou

Storm Hassell-Hart

Philip Carter

Laurence H Pearl

Robin L Owen

Raymond J Owens

S Mark Roe

Naomi E Chayen

Heinz-Josef Lenz

John Spencer

Chrisostomos Prodromou

Apostolos Klinakis

Justin Stebbing

Georgios Giamas

Affiliations

Soon will be listed here.

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.

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