Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping

• Published in: Nature reviews. Cancer Vol. 11; no. 10; pp. 708 - 718
• Main Authors: Kim, Sunghoon, You, Sungyong, Hwang, Daehee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2011; Nature Publishing Group
• Subjects: 631/208/199; 631/67; 692/420/755; Amino Acyl-tRNA Synthetases - genetics; Amino Acyl-tRNA Synthetases - metabolism; Aminoacyl-tRNA ligase; Aminoacyl-tRNA synthetases; analysis; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinogenesis; Humans; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Neoplastic Processes; Physiological aspects; Protein Binding; Protein biosynthesis; Signal Transduction; Stress; Tumorigenesis; South Korea
• ISSN: 1474-175X; 1474-1768; 1474-1768
• DOI: 10.1038/nrc3124

Key Points 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. Aminoacyl-tRNA synthetases (ARSs) are assumed to be simply 'housekeeping' genes. However, mammalian ARSs interact with diverse regulatory factors both inside and outside the cell. Do these enzymes have a role in tumorigenesis? 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.