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 Lee; Jung 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

doi:10.1038/nchembio.1381

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 journal › Article › peer-review

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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 language	English
Pages (from-to)	29-34
Number of pages	6
Journal	Nature Chemical Biology
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/nchembio.1381
Publication status	Published - 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.

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Molecular Biology
Cell Biology

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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

@article{912bf17f5a784e3c82fed6d8620362f3,

title = "Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction",

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.",

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

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.",

year = "2014",

month = jan,

doi = "10.1038/nchembio.1381",

language = "English",

volume = "10",

pages = "29--34",

journal = "Nature Chemical Biology",

issn = "1552-4450",

publisher = "Nature Publishing Group",

number = "1",

}

Kim, DG, Lee, JY, Kwon, NH, Fang, P, Zhang, Q, Wang, J, Young, NL, Guo, M, Cho, HY, Mushtaq, AU, Jeon, YH, Choi, JW, Han, JM, Kang, HW, Joo, JE, Hur, Y, Kang, W, Yang, H, Nam, DH, Lee, MS, Lee, JW, Kim, ES, Moon, A, Kim, K, Kim, D, Kang, EJ, Moon, Y, Rhee, KH, Han, BW, Yang, JS, Han, G, Yang, WS, Lee, C, Wang, MW & Kim, S 2014, 'Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction', Nature Chemical Biology, vol. 10, no. 1, pp. 29-34. https://doi.org/10.1038/nchembio.1381

TY - JOUR

T1 - Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction

AU - Kim, Dae Gyu

AU - Lee, Jin Young

AU - Kwon, Nam Hoon

AU - Fang, Pengfei

AU - Zhang, Qian

AU - Wang, Jing

AU - Young, Nicolas L.

AU - Guo, Min

AU - Cho, Hye Young

AU - Mushtaq, Ameeq Ul

AU - Jeon, Young Ho

AU - Choi, Jin Woo

AU - Han, Jung Min

AU - Kang, Ho Woong

AU - Joo, Jae Eun

AU - Hur, Youn

AU - Kang, Wonyoung

AU - Yang, Heekyoung

AU - Nam, Do Hyun

AU - Lee, Mi Sook

AU - Lee, Jung Weon

AU - Kim, Eun Sook

AU - Moon, Aree

AU - Kim, Kibom

AU - Kim, Doyeun

AU - Kang, Eun Joo

AU - Moon, Youngji

AU - Rhee, Kyung Hee

AU - Han, Byung Woo

AU - Yang, Jee Sun

AU - Han, Gyoonhee

AU - Yang, Won Suk

AU - Lee, Cheolju

AU - Wang, Ming Wei

AU - Kim, Sunghoon

N1 - 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.

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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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DO - 10.1038/nchembio.1381

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VL - 10

SP - 29

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JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 1

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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