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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Acknowledgements
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.
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D.G.K., J.Y.L. and S.K. designed experiments. D.G.K., J.Y.L., P.F., Q.Z., J.W., H.Y.C., A.U.M., J.W.C., H.W.K., J.E.J., W.K., H.Y., M.-S.L., E.-S.K., E.J.K., J.S.Y., W.S.Y. and J.S.Y. performed experiments. D.G.K., J.Y.L., N.H.K., N.L.Y., M.G., Y.H.J., H.W.K., Y.H., D.-H.N., J.W.L., A.M., J.M.H., G.H., C.L. and S.K. analyzed the data. Y.H., K.K., Y.M., D.K., K.H.R. and B.W.H. provided materials and supported experiments. D.G.K., N.H.K., M.G., Y.H.J., Y.H. and S.K. wrote the manuscript. D.G.K., J.Y.L., N.H.K., M.G., Y.H.J., H.W.K., Y.H., D.-H.N. and S.K. reviewed the manuscript. D.G.K., J.Y.L., N.H.K., M.G., Y.H.J., G.H., M.W.W. and S.K. discussed the results and commented.
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Kim, D., Lee, J., Kwon, N. et al. Chemical inhibition of prometastatic lysyl-tRNA synthetase–laminin receptor interaction. Nat Chem Biol 10, 29–34 (2014). https://doi.org/10.1038/nchembio.1381
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DOI: https://doi.org/10.1038/nchembio.1381
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