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

Research output: Contribution to journalArticlepeer-review

34 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

Bibliographical note

Funding Information:
This work was supported by the Global Frontier Project (grants NRF-M1AXA002-2010-0029785 (S.K.), NRF-M1AXA002-2010-0029765 (Y.H.J.), NRF-2012M3A6A4054271 (J.W.L.) and NRF-2012-054237 (B.W.H.)), the World Class University (grant R31-2008-000-10086-0 (G.H.)), the Proteogenomic Research Program (2012M3A9B9036679 (C.L.)) and by the National Research Foundation funded by the Ministry of Education, Science and Technology of Korea (grant ROA-2012-0006262 (A.M.)). This study was also funded by the Ministry for Health and Welfare Affairs of Korea through the Korea Healthcare Technology Research and Development Project (A092255 (D.-H.N.)) and by a grant from Gyeonggi Research Development Program (S.K.). This work was supported in part by grants from the US National Institutes of Health (GM100136 (M.G.)); the US National Science Foundation Division of Materials Research through DMR-11-57490 (A.G. Marshall, Florida State University); by the state of Florida (M.G.) and by a Kimmel Scholar Award for Cancer Research (M.G.). We appreciate A.G. Marshall for supporting the HDX-MS program and facility, M.-S. Seok (Korea University) for the preparation of the nanodisc and S.W. Lee (Sungkyunkwan University) for X-ray analysis.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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