Asparaginyl-tRNA Synthetase, a Novel Component of Hippo Signaling, Binds to Salvador and Enhances Yorkie-Mediated Tumorigenesis

Abstract

Aminoacyl-tRNA synthetases (ARSs), which are essential for protein translation, were recently shown to have non-translational functions in various pathological conditions including cancer. However, the molecular mechanism underlying the role of ARSs in cancer remains unknown. Here, we demonstrate that asparaginyl-tRNA synthetase (NRS) regulates Yorkie-mediated tumorigenesis by binding to the Hippo pathway component Salvador. NRS-RNAi and the NRS inhibitor tirandamycin B (TirB) suppressed Yorkie-mediated tumor phenotypes in Drosophila. Genetic analysis showed that NRS interacted with Salvador, and NRS activated Hippo target genes by regulating Yorkie phosphorylation. Biochemical analyses showed that NRS blocked Salvador-Hippo binding by interacting directly with Salvador, and TirB treatment inhibited NRS-Salvador binding. YAP target genes were upregulated in a mammalian cancer cell line with high expression of NRS, whereas TirB treatment suppressed cancer cell proliferation. These results indicate that NRS regulates tumor growth by interacting with Salvador in the Hippo signaling pathway.

Roles of Aminoacyl-tRNA Synthetases in Cancer

“…Zhong et al (2015) observed that IARS2 was highly expressed in human colon cancer tissues, and knockdown of IARS2 could inhibit RKO cell proliferation, suggesting that IARS2 might trigger the development of colon cancer. Furthermore, NRS induced Yorkie-mediated tumor phenotypes in a Drosophila model ( Yeom et al, 2020 ). During this process, NRS blocked the interaction between Salvador and Hippo by binding to Salvador, thereby activating Yorkie target genes via decreasing Yorkie phosphorylation ( Yeom et al, 2020 ).…”

“…Furthermore, NRS induced Yorkie-mediated tumor phenotypes in a Drosophila model ( Yeom et al, 2020 ). During this process, NRS blocked the interaction between Salvador and Hippo by binding to Salvador, thereby activating Yorkie target genes via decreasing Yorkie phosphorylation ( Yeom et al, 2020 ). Notably, YAP, a mammalian homolog of Yorkie, target genes were upregulated in colon cancer C26 cells, and NRS inhibitor TirB decreased the levels of YAP target genes and suppressed cell proliferation in C26 cells, indicating that NRS might regulate the development of colon cancer by Hippo signaling pathway ( Yeom et al, 2020 ).…”

“…During this process, NRS blocked the interaction between Salvador and Hippo by binding to Salvador, thereby activating Yorkie target genes via decreasing Yorkie phosphorylation ( Yeom et al, 2020 ). Notably, YAP, a mammalian homolog of Yorkie, target genes were upregulated in colon cancer C26 cells, and NRS inhibitor TirB decreased the levels of YAP target genes and suppressed cell proliferation in C26 cells, indicating that NRS might regulate the development of colon cancer by Hippo signaling pathway ( Yeom et al, 2020 ). Intriguingly, the hemizygous deletion of AIMP2 promoted epithelial cell proliferation and intestinal stem cell expansion in the intestinal crypt, which resulted in the formation of intestinal adenoma in Apc Min/+ mice ( Yum et al, 2016 ).…”

“…On the one hand, ARSs are involved in the progression of various cancers, such as colon cancer, lung cancer, breast cancer, gastric cancer and pancreatic cancer. Among them, some ARSs such as IARS2, KRS and NRS have been reported to promote the development of cancer ( Kim et al, 2012 ; Fang et al, 2018 ; Yeom et al, 2020 ), while AIMPs, SerRS and GRS usually exert anti-tumor effects ( Park et al, 2012 ; Li Y. et al, 2019 ; Zhou Z. et al, 2020 ). On the other hand, ARSs can be used not only as biomarkers for cancer diagnosis and prognosis, but also as potential targets for inhibiting cancer growth and metastasis.…”

“…Strikingly, ARSs and AIMPs are closely related to tumorigenesis ( Yin et al, 2016 ; Gao et al, 2019 ; Zhou Z. et al, 2020 ). Certain ARSs, such as isoleucyl-tRNA synthetase 2 (IARS2), lysyl-tRNA synthetase (KRS) and asparaginyl-tRNA synthetase (NRS), have been shown to promote cancer development ( Kim et al, 2012 ; Fang et al, 2018 ; Yeom et al, 2020 ), while AIMPs and seryl-tRNA synthetase (SerRS) usually exert anti-tumor effects ( Li Y. et al, 2019 ; Zhou Z. et al, 2020 ). Furthermore, some ARSs are abnormally expressed in various cancer tissues and have diagnostic and prognostic value ( Jung et al, 2017 ; Lee and Kim, 2019 ).…”