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

  • Nat Chem Biol. 2014 Jan;10(1):29-34. doi: 10.1038/nchembio.1381.
Dae Gyu Kim  1 ,  Jin Young Lee  1 ,  Nam Hoon Kwon  2 ,  Pengfei Fang  3 ,  Qian Zhang  4 ,  Jing Wang  3 ,  Nicolas L Young  5 ,  Min Guo  3 ,  Hye Young Cho  6 ,  Ameeq Ul Mushtaq  6 ,  Young Ho Jeon  6 ,  Jin Woo Choi  7 ,  Jung Min Han  2 ,  Ho Woong Kang  8 ,  Jae Eun Joo  8 ,  Youn Hur  8 ,  Wonyoung Kang  9 ,  Heekyoung Yang  9 ,  Do-Hyun Nam  9 ,  Mi-Sook Lee  10 ,  Jung Weon Lee  10 ,  Eun-Sook Kim  11 ,  Aree Moon  11 ,  Kibom Kim  2 ,  Doyeun Kim  2 ,  Eun Joo Kang  12 ,  Youngji Moon  12 ,  Kyung Hee Rhee  10 ,  Byung Woo Han  10 ,  Jee Sun Yang  13 ,  Gyoonhee Han  13 ,  Won Suk Yang  2 ,  Cheolju Lee  14 ,  Ming-Wei Wang  15 ,  Sunghoon Kim  16
Affiliations
  • 1. 1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. [3].
  • 2. 1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
  • 3. Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA.
  • 4. Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, USA.
  • 5. Ion Cyclotron Resonance Program, National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida, USA.
  • 6. College of Pharmacy, Korea University, Sejong, Korea.
  • 7. 1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 8. Yuhan Research Institute, Yongin, Korea.
  • 9. Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 10. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
  • 11. College of Pharmacy, Duksung Women's University, Seoul, Korea.
  • 12. Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea.
  • 13. Translational Research Center for Protein Function Control, Department of Biotechnology and WCU Department of Biomedical Sciences, Yonsei University, Seoul, Korea.
  • 14. BRI, Korea Institute of Science and Technology, Seoul, Korea.
  • 15. The National Center for Drug Screening, Zhangjiang High-Tech Park, Shanghai, China.
  • 16. 1] 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.
PMID: 24212136 DOI: 10.1038/nchembio.1381
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.

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