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Nat Chem Biol. 2014 Jan;10(1):29-34. doi: 10.1038/nchembio.1381. Epub 2013 Nov 10.

Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction.

Author information

  • 11] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. [3].
  • 21] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
  • 3Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA.
  • 4Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, USA.
  • 5Ion Cyclotron Resonance Program, National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida, USA.
  • 6College of Pharmacy, Korea University, Sejong, Korea.
  • 71] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 8Yuhan Research Institute, Yongin, Korea.
  • 9Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 10Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
  • 11College of Pharmacy, Duksung Women's University, Seoul, Korea.
  • 12Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea.
  • 13Translational Research Center for Protein Function Control, Department of Biotechnology and WCU Department of Biomedical Sciences, Yonsei University, Seoul, Korea.
  • 14BRI, Korea Institute of Science and Technology, Seoul, Korea.
  • 15The National Center for Drug Screening, Zhangjiang High-Tech Park, Shanghai, China.
  • 161] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. [3] World Class University Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.

Abstract

Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a laminin signal and stabilizes a 67-kDa laminin receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds KRS, impinged on the interaction of KRS with 67LR and suppressed metastasis in three different mouse models. The compound inhibited the KRS-67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS-67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.

PMID:
24212136
[PubMed - indexed for MEDLINE]
PMCID:
PMC4021855
Free PMC Article
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