Aminoacyl-tRNA synthetases (ARSs) are 'housekeeping' proteins that are involved in protein translation. They catalyse the ligation of amino acids to their cognate tRNAs with a high fidelity. Mammalian members of this family have additional domains that enable them to interact with various proteins, some of which are implicated in tumorigenesis.
Eight ARSs form a macromolecular protein complex with three auxiliary factors, designated ARS-interacting multifunctional protein 1 (AIMP1), AIMP2 and AIMP3. This complex is known as the multisynthatase complex (MSC).
On genotoxic damage, AIMP2 and AIMP3 are translocated to the nucleus where AIMP2 activates p53 directly and AIMP3 activates p53 through the activation of the kinases ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR).
AIMP2 augments the apoptotic signal of tumour necrosis factor (TNF) through the downregulation of TNF receptor associated factor 2 (TRAF2) and mediates the transforming growth factor-β anti-proliferative signal through the downregulation of fuse-binding protein (FBP). A splice variant of AIMP2, AIMP2-DX2, compromises the tumour suppressive activity of AIMP2 and can induce tumorigenesis.
Among the ARSs that form the MSC, bifunctional glutamyl-prolyl-tRNA synthetase (EPRS) can function as a translational silencer to suppress the generation of vascular endothelial growth factor A. Lysyl-tRNA synthetase (KRS) can translocate to the nucleus to bind microphthalmia-associated transcription factor, which is an oncogenic transcriptional activator that is implicated in the development of melanoma. KRS is also secreted and induces the production of TNF from macrophages. Glutaminyl-tRNA synthetase (QRS) can interact with apoptosis signal-regulating kinase 1 to suppress apoptotic signals in a glutamine-dependent manner, and MRS can increase ribosomal RNA biogenesis in the nucleoli.
Among free-form ARSs, tryptophanyl-tRNA synthetase (WRS) is secreted, and the truncation of the amino-terminal peptide generates an active cytokine that suppresses angiogenesis. Tyrosyl-tRNA synthetase (YRS) is also secreted and cleaved into N- and C-domains that have pro-angiogenic and immune activation functions, respectively. The C-terminal domain of human YRS is homologous to endothelial-monocyte-activating polypeptide II (EMAPII), which is the C-terminal domain of AIMP1. This functions as an immune-stimulating cytokine that is crucial for the chemotaxis of mononuclear phagocytes and polymorphonuclear leukocytes, and the production of TNF, tissue factor and myeloperoxidase.
A systematic analysis of the expression of ARSs and AIMPs (ARSN) indicates that these proteins are associated with cancer, and a network model identifies some of the links between ARSN and 123 first neighbour cancer-associated genes.
Over the past decade, the identification of cancer-associated factors has been a subject of primary interest not only for understanding the basic mechanisms of tumorigenesis but also for discovering the associated therapeutic targets. However, aminoacyl-tRNA synthetases (ARSs) have been overlooked, mostly because many assumed that they were simply 'housekeepers' that were involved in protein synthesis. Mammalian ARSs have evolved many additional domains that are not necessarily linked to their catalytic activities. With these domains, they interact with diverse regulatory factors. In addition, the expression of some ARSs is dynamically changed depending on various cellular types and stresses. This Analysis article addresses the potential pathophysiological implications of ARSs in tumorigenesis.
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This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (NRF-2008-359-C00024), the Global Frontier Project grant (NRF-M1AXA002-2010-0029785) and by [R31-2008-000-10103-0] and [R31-2008-000-10105-0] from the World Class University project of the Ministry of Education, Science and Technology.
The authors declare no competing financial interests.
Selection of cancer-associated genes (PDF 66 kb)
3501 Cancer-associated genes (CAGs) and interactors of ARSs and AIMPs (XLS 953 kb)
Identification of the CAGs directly interacting with ARSs and AIMPs (PDF 97 kb)
644 interactions of ARSs and AIMPs (XLS 135 kb)
Non-cancer-associated genes (non-CAGs) (XLS 2805 kb)
40 cancer-associated mRNA datasets (XLS 21 kb)
Similarity comparison in the expression profiles of ARSN, CAGs and non-CAGs (PDF 130 kb)
Copy number variations obtained from Tumorscape (PDF 95 kb)
Phsphorylated sites of ARS and AIMPs (XLS 42 kb)
Cancer association scores of ARSs and AIMPs in the network (PDF 95 kb)
Association of ARSs and AIMPs with biological processes and cancer types (PDF 93 kb)
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Kim, S., You, S. & Hwang, D. Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping. Nat Rev Cancer 11, 708–718 (2011). https://doi.org/10.1038/nrc3124
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