Roles of Aminoacyl-tRNA Synthetases in Cancer

Abstract

Aminoacyl-tRNA synthetases (ARSs) catalyze the ligation of amino acids to their cognate transfer RNAs (tRNAs), thus playing an important role in protein synthesis. In eukaryotic cells, these enzymes exist in free form or in the form of multi-tRNA synthetase complex (MSC). The latter contains nine cytoplasmic ARSs and three ARS-interacting multifunctional proteins (AIMPs). Normally, ARSs and AIMPs are regarded as housekeeping molecules without additional functions. However, a growing number of studies indicate that ARSs are involved in a variety of physiological and pathological processes, especially tumorigenesis. Here, we introduce the roles of ARSs and AIMPs in certain cancers, such as colon cancer, lung cancer, breast cancer, gastric cancer and pancreatic cancer. Furthermore, we particularly focus on their potential clinical applications in cancer, aiming at providing new insights into the pathogenesis and treatment of cancer.

Keywords: ARS-interacting multifunctional protein; aminoacyl-tRNA synthetase; cancer; pathogenesis; therapeutics.

FIGURE 1

Common pathways mediated by ARSs in cancer development. KRS is phosphorylated by p38/MAPK and then dissociates from the MSC. Subsequently, the KRS interacts with 67LR that is localized in the cell membrane, which prevents NEDD4 from ubiquitinating 67LR and enhances laminin-induced cell migration. Moreover, KRS forms a complex with 67LR and integrin α6β1 to mediate ERKs/c-Jun activation and paxillin expression. MRS increases the lysine homocysteinylation of ATR, thereby inhibiting ATR and its downstream CHK1 and p53. AIMP2-DX2 reduces the pro-apoptotic activity of AIMP2 by competitively binding to p53 with AIMP2. Furthermore, MRS is phosphorylated by GCN2, resulting in a conformational change of MRS and subsequent dissociation of AIMP3 from the MSC. The released AIMP3 interacts with ATM/ATR to up-regulate the expression of p53, thereby responding to DNA damage. ARSs, aminoacyl-tRNA synthetases; AIMPs, ARS-interacting multifunctional proteins; KRS, lysyl-tRNA synthetase; MAPK, mitogen-activated protein kinase; MSC, multi-tRNA synthetase complex; 67LR, 67-kDa laminin receptor; NEDD4, neural precursor cell expressed developmentally downregulated 4; ERKs, extracellular signal-regulated kinases; MRS, methionyl-tRNA synthetase; ATR, ataxia telangiectasia and Rad3-related protein; CHK1, checkpoint kinase-1; AIMP2-DX2, AIMP2 lacking exon 2; GCN2, general control non-repressed-2; ATM, ataxia telangiectasia-mutated.

FIGURE 2

Roles of ARSs and AIMPs in the biology of colon cancer. KRS translocates to the nucleus and then induces GAS6 transcription by activating MiTF, which promotes the M2 polarization of neighboring macrophages and then facilitates cancer metastasis. KRS-containing exosomes are released by cancer cells and then induce M1 polarization and migration of macrophages. NRS blocks the interaction between Salvador and Hippo by binding to Salvador, thereby activating Yorkie target genes via decreasing Yorkie phosphorylation. AIMP2 blocks the interaction between DVL1 and AXIN and thus inhibits the activity of Wnt/β-catenin signaling. ARSs, aminoacyl-tRNA synthetases; AIMPs, ARS-interacting multifunctional proteins; KRS, lysyl-tRNA synthetase; MiTF, microphthalmia-associated transcription factor; GAS6, growth arrest-specific 6; NRS, asparaginyl-tRNA synthetase; DVL1, disheveled-1; AXIN, axis inhibition protein.

FIGURE 3

Roles of AIMP2 and AIMP2-DX2 in the development of lung cancer. AIMP2 dissociates from the MSC and translocates to the nucleus. The nuclear AIMP2 interacts with Smurf2, thereby enhancing FBP ubiquitination and down-regulating c-Myc. Meanwhile, the interaction also inhibits the binding of Smurf2 to CRM1, which enhances TGF-β signal by reducing the nuclear output of Smurf2. HSP70 inhibits the Siah1-dependent AIMP2-DX2 ubiquitination by interacting with AIMP2-DX2, thereby maintaining the stabilization of AIMP2-DX2. AIMP2-DX2 inhibits p14/ARF by directly binding to it, thereby suppressing oncogene-induced apoptosis and senescence. AIMP2, ARS-interacting multifunctional protein 2; AIMP2-DX2, AIMP2 lacking exon 2; MSC, multi-tRNA synthetase complex; MAPK, mitogen-activated protein kinase; Smurf2, Smad ubiquitin regulatory factors 2; FBP, FUSE-binding protein; CRM1, chromosomal region maintenance 1; TGF-β, transforming growth factor-β; HSP70, heat shock protein 70; Siah1, Seven in absentia homolog 1.

FIGURE 4

Aminoacyl-tRNA synthetases and potential therapeutic applications. (A) BC-LI-0186 binds to the RagD interacting site of LRS, thus suppressing the lysosomal localization and activity of mTORC1. (B) BC-DXI-843 promotes the degradation of AIMP2-DX2 by blocking the interaction between AIMP2-DX2 and HSP70, thereby inducing cancer cell apoptosis. (C) BC-K-YH16899 not only blocks the interaction of KRS and 67LR by binding to KRS, but also reduces the KRS membrane localization by restraining the flexible N-ext of KRS. (D) Macrophages secretes GRS under the stimulation of Fas ligand released by tumor cells. The secreted GRS interacts with specific ERK-activated tumor cells through CDH6, thereby enhancing PP2A activity by releasing PP2A from CDH6. The activated PP2A inhibits ERK signaling by binding to ERK and thus induces apoptosis of cancer cells. (E) AIMP1 inhibits the lung metastasis of melanoma cells in mice through macrophage-mediated activation of NK cells. AIMP1 induces macrophages to produce TNF-α, which partially activates NK cells. Meanwhile, the activation of NK cells requires the direct contact between NK cells and macrophages. (F) The knockdown of RARS-MAD1L1 using siRARS-005 or siMAD1L1-003 inhibits cancer development by suppressing FBP/c-Myc pathway. ARSs, aminoacyl-tRNA synthetases; LRS, leucyl-tRNA synthetase; mTORC1, mammalian target of rapamycin complex 1; AIMP2-DX2, AIMP2 lacking exon 2; HSP70, heat shock protein 70; KRS, lysyl-tRNA synthetase; 67LR, 67-kDa laminin receptor; GRS, glycyl-tRNA synthetase; CDH6, cadherin-6; PP2A, phosphatase 2A; ERK, extracellular signal-regulated kinase; AIMP1, ARS-interacting multifunctional protein 1; TNF-α, tumor necrosis factor α; NK cell, natural killer cell; RARS, arginyl-tRNA synthetase; MAD1L1, mitotic arrest deficient 1-like 1; FBP, FUSE-binding protein.