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.

• Authors: 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
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 10 Issue 1 Pg. 29-34 (Jan 2014) ISSN: 1552-4469 [Electronic] United States
• PMID: 24212136 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Receptors, Laminin
• Lysine-tRNA Ligase

Topics

• Cell Membrane (metabolism)
• Lysine-tRNA Ligase (antagonists & inhibitors, metabolism)
• Neoplasm Metastasis
• Protein Transport
• Receptors, Laminin (antagonists & inhibitors, metabolism)