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

Dae Gyu Kim, Jin Young Lee, Nam Hoon Kwon, Pengfei Fang, Qian Zhang, Jing Wang, Nicolas L. Young, Min Guo, Hye Young Cho, Ameeq Ul Mushtaq, Young Ho Jeon, Jin Woo Choi, Jung Min Han, Ho Woong Kang, Jae Eun Joo, Youn Hur, Wonyoung Kang, Heekyoung Yang, Do Hyun Nam, Mi Sook LeeJung Weon Lee, Eun Sook Kim, Aree Moon, Kibom Kim, Doyeun Kim, Eun Joo Kang, Youngji Moon, Kyung Hee Rhee, Byung Woo Han, Jee Sun Yang, Gyoonhee Han, Won Suk Yang, Cheolju Lee, Ming Wei Wang, Sunghoon Kim

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29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)29-34
Number of pages6
JournalNature Chemical Biology
Volume10
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Kim, D. G., Lee, J. Y., Kwon, N. H., Fang, P., Zhang, Q., Wang, J., Young, N. L., Guo, M., Cho, H. Y., Mushtaq, A. U., Jeon, Y. H., Choi, J. W., Han, J. M., Kang, H. W., Joo, J. E., Hur, Y., Kang, W., Yang, H., Nam, D. H., ... Kim, S. (2014). Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction. Nature Chemical Biology, 10(1), 29-34. https://doi.org/10.1038/nchembio.1381