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Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping

Nature Reviews Cancer volume 11, pages 708–718 (2011)Cite this article

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An Erratum to this article was published on 28 September 2011

This article has been updated

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.

Abstract

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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Figure 1: Catalytic activity of ARSs.
Figure 2: Non-canonical activities of ARSs and AIMPs implicated in the control of tumorigenesis.
Figure 3: Expression profiles and copy number variations of ARS-encoding genes in comparison to CAGs and non-CAGs.
Figure 4: Hypothetical network model showing connections of ARSs and AIMPs with their CAG interactors.

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Change history

  • 28 September 2011

    In Figure 4c of this article, data for AIMP1-3 were all mistakenly labelled as AIMP3. This has now been corrected online.

References

  1. Guo, M., Yang, X. L. & Schimmel, P. New functions of aminoacyl-tRNA synthetases beyond translation. Nature Rev. Mol. Cell Biol. 11, 668–674, (2010).

    Article  CAS  Google Scholar 

  2. Park, S. G., Ewalt, K. L. & Kim, S. Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers. Trends Biochem. Sci. 30, 569–574 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Park, S. G., Schimmel, P. & Kim, S. Aminoacyl tRNA synthetases and their connections to disease. Proc. Natl Acad. Sci. USA 105, 11043–11049 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shin, S. H. et al. Implication of leucyl-tRNA synthetase 1 (LARS1) overexpression in growth and migration of lung cancer cells detected by siRNA targeted knock-down analysis. Exp. Mol. Med. 40, 229–236 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vellaichamy, A. et al. Proteomic interrogation of androgen action in prostate cancer cells reveals roles of aminoacyl tRNA synthetases. PLoS ONE 4, e7075 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Kushner, J. P., Boll, D., Quagliana, J. & Dickman, S. Elevated methionine-tRNA synthetase activity in human colon cancer. Proc. Soc. Exp. Biol. Med. 153, 273–276 (1976).

    Article  CAS  PubMed  Google Scholar 

  7. Marshall, L., Kenneth, N. S. & White, R. J. Elevated tRNAiMet synthesis can drive cell proliferation and oncogenic transformation. Cell 133, 78–89, (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Forus, A., Florenes, V. A., Maelandsmo, G. M., Fodstad, O. & Myklebost, O. The protooncogene CHOP/GADD153, involved in growth arrest and DNA damage response, is amplified in a subset of human sarcomas. Cancer Genet. Cytogenet. 78, 165–171 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Nilbert, M., Rydholm, A., Mitelman, F., Meltzer, P. S. & Mandahl, N. Characterization of the 12q13–15 amplicon in soft tissue tumours. Cancer Genet. Cytogenet. 83, 32–36 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Palmer, J. L., Masui, S., Pritchard, S., Kalousek, D. K. & Sorensen, P. H. Cytogenetic and molecular genetic analysis of a pediatric pleomorphic sarcoma reveals similarities to adult malignant fibrous histiocytoma. Cancer Genet. Cytogenet. 95, 141–147 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Reifenberger, G. et al. Refined mapping of 12q13-q15 amplicons in human malignant gliomas suggests CDK4/SAS and MDM2 as independent amplification targets. Cancer Res. 56, 5141–5145 (1996).

    CAS  PubMed  Google Scholar 

  12. Ron, D. & Habener, J. F. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev. 6, 439–453 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Savant-Bhonsale, S. & Cleveland, D. W. Evidence for instability of mRNAs containing AUUUA motifs mediated through translation-dependent assembly of a >20S degradation complex. Genes Dev. 6, 1927–1939 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Ubeda, M., Schmitt-Ney, M., Ferrer, J. & Habener, J. F. CHOP/GADD153 and methionyl-tRNA synthetase (MetRS) genes overlap in a conserved region that controls mRNA stability. Biochem. Biophys. Res. Commun. 262, 31–38 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Park, S. W., Kim, S. S., Yoo, N. J. & Lee, S. H. Frameshift mutation of MARS gene encoding an aminoacyl-tRNA Synthetase in gastric and colorectal carcinomas with microsatellite instability. Gut Liver 4, 430–431 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bullock, A. N. & Fersht, A. R. Rescuing the function of mutant p53. Nature Rev. Cancer 1, 68–76 (2001).

    Article  CAS  Google Scholar 

  17. Kaufman, R. J. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110, 1389–1398 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ma, Y. & Hendershot, L. M. The role of the unfolded protein response in tumour development: friend or foe? Nature Rev. Cancer 4, 966–977 (2004).

    Article  CAS  Google Scholar 

  19. Lee, J. W. et al. Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 443, 50–55 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Nicolaides, N. C., Kinzler, K. W. & Vogelstein, B. Analysis of the 5′ region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene. Genomics 29, 329–334 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Han, J. M. et al. Hierarchical network between the components of the multi-tRNA synthetase complex: implications for complex formation. J. Biol. Chem. 281, 38663–38667 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Park, S. G., Choi, E. C. & Kim, S. Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMPs): a triad for cellular homeostasis. IUBMB Life 62, 296–302 (2010).

    CAS  PubMed  Google Scholar 

  23. Ray, P. S., Arif, A. & Fox, P. L. Macromolecular complexes as depots for releasable regulatory proteins. Trends Biochem. Sci. 32, 158–164 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Quevillon, S., Robinson, J.-C., Berthonneau, E., Siatecka, M. & Mirande, M. Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of protein-protein interactions and characterization of a core protein. J. Mol. Biol. 285, 183–195 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Quevillon, S. & Mirande, M. The p18 component of the multisynthetase complex shares a protein motif with the β and γ subunits of eukaryotic elongation factor 1. FEBS Lett. 395, 63–67 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Kim, J. Y. et al. p38 is essential for the assembly and stability of macromolecular tRNA synthetase complex: implications for its physiological significance. Proc. Natl Acad. Sci. USA 99, 7912–7916 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Park, S. G. et al. Precursor of pro-apoptotic cytokine modulates aminoacylation activity of tRNA synthetase. J. Biol. Chem. 274, 16673–16676 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Nicolaides, N. C. et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75–80 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Guzzo, C. M. & Yang, D. C. Lysyl-tRNA synthetase interacts with EF1α, aspartyl-tRNA synthetase and p38 in vitro. Biochem. Biophys. Res. Commun. 365, 718–723 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Ahn, H. C., Kim, S. & Lee, B. J. Solution structure and p43 binding of the p38 leucine zipper motif: coiled-coil interactions mediate the association between p38 and p43. FEBS Lett. 542, 119–124 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Kim, M. J. et al. Downregulation of fuse-binding protein and c-myc by tRNA synthetase cofactor, p38, is required for lung differentiation. Nature Genet. 34, 330–336 (2003). This paper provides evidence that AIMP2 functions in the growth-arresting signal of TGFβ and the significance of this in lung development.

    Article  CAS  PubMed  Google Scholar 

  32. Duncan, R. et al. A sequence-specific, single-strand binding protein activates the far upstream element of c-myc and defines a new DNA-binding motif. Genes Dev. 8, 465–480 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Davis-Smyth, T., Duncan, R. C., Zheng, T., Michelotti, G. & Levens, D. The far upstream element-binding proteins comprise an ancient family of single-strand DNA-binding transactivators. J. Biol. Chem. 271, 31679–31687 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Choi, J. W. et al. AIMP2/p38 promotes TNF-α-dependent apoptosis via ubiquitin-mediated degradation of TRAF2. J. Cell Sci. 122, 2710–2715 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Li, X., Yang, Y. & Ashwell, J. D. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 416, 345–347 (2002).

    Article  PubMed  Google Scholar 

  36. Han, J. M. et al. AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53. Proc. Natl Acad. Sci. USA 105, 11206–11211 (2008). This paper illustrates that AIMP2 is a key mediator of apoptosis in response to DNA damage through the activation of p53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang, Z. & Li, B. Mdm2 links genotoxic stress and metabolism to p53. Protein Cell 1, 1063–1072 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Choi, J. W., Um, J. Y., Kundu, J. K., Surh, Y. J. & Kim, S. Multidirectional tumour-suppressive activity of AIMP2/p38 and the enhanced susceptibility of AIMP2 heterozygous mice to carcinogenesis. Carcinogenesis 30, 1638–1644 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Choi, J. W. et al. Cancer-associated splicing variant of tumour suppressor AIMP2/p38: pathological implication in tumorigenesis. Plos Genet. 7, e1101351 (2011). This paper describes an oncogenic variant of AIMP2 in lung cancer and its potential as a therapeutic target and a prognostic marker for patient survival.

  40. Park, B. J. et al. The haploinsufficient tumour suppressor p18 upregulates p53 via interactions with ATM/ATR. Cell 120, 209–221 (2005). This paper demonstrates the importance of AIMP3 as a potent tumor suppressor through the activation of ATM and ATR, which are kinases upstream of p53.

    Article  CAS  PubMed  Google Scholar 

  41. Park, B. J. et al. AIMP3 haploinsufficiency disrupts oncogene-induced p53 activation and genomic stability. Cancer Res. 66, 6913–6918 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Kim, K. J. et al. Determination of three dimensional structure and residues of novel tumour suppressor, AIMP3/p18, required for the interaction with ATM. J. Biol. Chem. (2008).

  43. Oh, Y. S. et al. Downregulation of lamin A by tumour suppressor AIMP3/p18 leads to a progeroid phenotype in mice. Aging Cell 9, 810–822 (2010). This paper shows that AIMP3 can control the ageing process through the downregulation of lamin A and suggests a potential connection between tumorigenesis and senescence.

    Article  CAS  PubMed  Google Scholar 

  44. Levy, C. & Fisher, D. E. Dual roles of lineage restricted transcription factors: The case of MITF in melanocytes. Transcription 2, 19–22 (2011).

    Article  PubMed  Google Scholar 

  45. Razin, E. et al. Suppression of microphthalmia transcriptional activity by its association with protein kinase C-interacting protein 1 in mast cells. J. Biol. Chem. 274, 34272–34276 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Ruggero, D. & Pandolfi, P. P. Does the ribosome translate cancer? Nature Rev. Cancer 3, 179–192 (2003).

    Article  CAS  Google Scholar 

  47. Drygin, D. et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumour growth. Cancer Res. 71, 1418–1430 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Ko, Y. G., Kang, Y. S., Kim, E. K., Park, S. G. & Kim, S. Nucleolar localization of human methionyl-tRNA synthetase and its role in ribosomal RNA synthesis. J. Cell Biol. 149, 567–574 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chen, Z. et al. ASK1 mediates apoptotic cell death induced by genotoxic stress. Oncogene 18, 173–180 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Ko, Y.-G. et al. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1. J. Biol. Chem. 276, 6030–6036 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Rho, S. B. et al. A multifunctional repeated motif is present in human bifunctional tRNA synthetase. J. Biol. Chem. 273, 11267–11273 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Sampath, P. et al. Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation. Cell 119, 195–208 (2004). This paper illustrates the translational silencing activity of human glutamyl-prolyl-tRNA synthetase outside the translational machinery.

    Article  CAS  PubMed  Google Scholar 

  53. Ray, P. S. et al. A stress-responsive RNA switch regulates VEGFA expression. Nature 457, 915–919 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Arif, A., Jia, J., Moodt, R. A., DiCorleto, P. E. & Fox, P. L. Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control. Proc. Natl Acad. Sci. USA 108, 1415–1420 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mukhopadhyay, R., Jia, J., Arif, A., Ray, P. S. & Fox, P. L. The GAIT system: a gatekeeper of inflammatory gene expression. Trends Biochem. Sci. 34, 324–331 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tolstrup, A. B., Bejder, A., Fleckner, J. & Justesen, J. Transcriptional regulation of the interferon-γ-inducible tryptophanyl-tRNA synthetase includes alternative splicing. J. Biol. Chem. 270, 397–403 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Turpaev, K. T. et al. Alternative processing of the tryptophanyl-tRNA synthetase mRNA from interferon-treated human cells. Eur. J. Biochem. 240, 732–737 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Wakasugi, K. et al. A human aminoacyl-tRNA synthetase as a regulator of angiogenesis. Proc. Natl Acad. Sci. USA 99, 173–177 (2002). This paper shows that a truncated peptide derived from human tryptophanyl-tRNA synthetase is secreted as a cytokine to control angiogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kapoor, M. et al. Evidence for annexin II-S100A10 complex and plasmin in mobilization of cytokine activity of human TrpRS. J. Biol. Chem. 283, 2070–2077 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Tzima, E. et al. VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function. J. Biol. Chem. 280, 2405–2408 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Kise, Y. et al. A short peptide insertion crucial for angiostatic activity of human tryptophanyl-tRNA synthetase. Nature Struct. Mol. Biol. 11, 149–156 (2004). This paper illustrates the structural feature for the angiostatic cytokine activity of human tryptophanyl-tRNA synthetase.

    Article  CAS  Google Scholar 

  62. Ghanipour, A. et al. The prognostic significance of tryptophanyl-tRNA synthetase in colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 18, 2949–2956 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Wakasugi, K. & Schimmel, P. Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science 284, 147–151 (1999). This paper reports novel cytokine activities derived from secreted human tyrosyl-tRNA synthetase.

    Article  CAS  PubMed  Google Scholar 

  64. Wakasugi, K. et al. Induction of angiogenesis by a fragment of human tyrosyl-tRNA synthetase. J. Biol. Chem. 277, 20124–20126 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Hebert, C. A., Vitangcol, R. V. & Baker, J. B. Scanning mutagenesis of interleukin-8 identifies a cluster of residues required for receptor binding. J. Biol. Chem. 266, 18989–18994 (1991).

    CAS  PubMed  Google Scholar 

  66. Yang, X. L., Skene, R. J., McRee, D. E. & Schimmel, P. Crystal structure of a human aminoacyl-tRNA synthetase cytokine. Proc. Natl Acad. Sci. USA 99, 15369–15374 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Greenberg, Y. et al. The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells. FASEB J. 22, 1597–1605 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Wakasugi, K. & Schimmel, P. Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase. J. Biol. Chem. 274, 23155–23159 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Park, S. G. et al. Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response. Proc. Natl Acad. Sci. USA 102, 6356–6361 (2005). This paper identifies a potent pro-inflammatory cytokine activity for human lysyl-tRNA synthetase secreted from cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Levine, S. M., Rosen, A. & Casciola-Rosen, L. A. Anti-aminoacyl tRNA synthetase immune responses: insights into the pathogenesis of the idiopathic inflammatory myopathies. Curr. Opin. Rheumatol 15, 708–713 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Kao, J. et al. Endothelial monocyte-activating polypeptide II: a novel tumour-derived polypeptide that activates host-response mechanisms. J. Biol. Chem. 267, 20239–20247 (1992).

    CAS  PubMed  Google Scholar 

  72. Ko, Y.-G. et al. A cofactor of tRNA synthetase, p43, is secreted to upregulate proinflammatory genes. J. Biol. Chem. 276, 23028–32303 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Han, J. M., Heejoon, M. & Kim, S. Antitumour activity and pharmacokinetic properties of ARS-interacting multi-functional protein 1 (AIMP1/p43). Cancer Lett. 287, 157–164 (2009).

    Article  PubMed  CAS  Google Scholar 

  74. Lee, Y. S. et al. Antitumour activity of the novel human cytokine AIMP1 in an in vivo tumour model. Mol. Cells 21, 213–217 (2006).

    CAS  PubMed  Google Scholar 

  75. Park, S. G. et al. Dose-dependent biphasic activity of tRNA synthetase-associating factor, p43, in angiogenesis. J. Biol. Chem. 277, 45243–45248 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Kim, E., Kim, S. H., Kim, S. & Kim, T. S. The novel cytokine p43 induces IL-12 production in macrophages via NF-κB activation, leading to enhanced IFN-γ production in CD4+ T cells. J. Immunol. 176, 256–264 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Kim, E., Kim, S. H., Kim, S., Cho, D. & Kim, T. S. AIMP1/p43 protein induces the maturation of bone marrow-derived dendritic cells with T helper type 1-polarizing ability. J. Immunol. 180, 2894–2902 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Kim, T. S., Lee, B. C., Kim, E., Cho, D. & Cohen, E. P. Gene transfer of AIMP1 and B7.1 into epitope-loaded, fibroblasts induces tumour-specific CTL immunity, and prolongs the survival period of tumour-bearing mice. Vaccine 26, 5928–5934 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. van Horssen, R., Eggermont, A. M. & ten Hagen, T. L. Endothelial monocyte-activating polypeptide-II and its functions in (patho)physiological processes. Cytokine Growth Factor Rev. 17, 339–348 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Chang, S. Y., Park, S. G., Kim, S. & Kang, C. Y. Interaction of the C-terminal domain of p43 and the α subunit of ATP synthase. Its functional implication in endothelial cell proliferation. J. Biol. Chem. 277, 8388–8394 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Li, Z., Liu, Y. H., Xue, Y. X., Xie, H. & Liu, L. B. Role of ATP synthase α subunit in low-dose endothelial monocyte-activating polypeptide-II-induced opening of the blood-tumour barrier. J. Neurol. Sci. 300, 52–58 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Hou, Y. et al. Endothelial-monocyte-activating polypeptide II induces migration of endothelial progenitor cells via the chemokine receptor CXCR3. Exp. Haematol. 34, 1125–1132 (2006).

    Article  CAS  Google Scholar 

  83. Barrett, T. et al. NCBI GEO: archive for high-throughput functional genomic data. Nucleic Acids Res. 37, D885–D890 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Parkinson, H. et al. ArrayExpress—a public database of microarray experiments and gene expression profiles. Nucleic Acids Res. 35, D747–D750 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Lee, H. J. et al. Direct transfer of α-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J. Biol. Chem. 285, 9262–9272 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hwang, D. et al. A data integration methodology for systems biology. Proc. Natl Acad. Sci. USA 102, 17296–17301 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Scheinin, I. et al. CanGEM: mining gene copy number changes in cancer. Nucleic Acids Res. 36, D830–D835 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gnad, F., Gunawardena, J. & Mann, M. PHOSIDA 2011: the posttranslational modification database. Nucleic Acids Res. 39, D253–D260 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Hornbeck, P. V., Chabra, I., Kornhauser, J. M., Skrzypek, E. & Zhang, B. PhosphoSite: a bioinformatics resource dedicated to physiological protein phosphorylation. Proteomics 4, 1551–1561 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Junker, B. H., Koschutzki, D. & Schreiber, F. Exploration of biological network centralities with CentiBiN. BMC Bioinformatics 7, 219 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Zhou, X., Kao, M. C. & Wong, W. H. Transitive functional annotation by shortest-path analysis of gene expression data. Proc. Natl Acad. Sci. USA 99, 12783–12788 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Stuart, J. M., Segal, E., Koller, D. & Kim, S. K. A gene-coexpression network for global discovery of conserved genetic modules. Science 302, 249–255 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Lee, H. K., Hsu, A. K., Sajdak, J., Qin, J. & Pavlidis, P. Coexpression analysis of human genes across many microarray data sets. Genome Res. 14, 1085–1094 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Horvath, S. & Dong, J. Geometric interpretation of gene coexpression network analysis. PLoS Comput. Biol. 4, e1000117 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Albert, R., Barabasi, A.-L. Statistical mechanics of complex networks. Rev. Modern Phys. 74, 47–92 (2002).

    Article  Google Scholar 

  97. Han, J. M. et al. Identification of gp96 as a novel target for treatment of autoimmune disease in mice. PLoS ONE 5, e9792 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Schwarz, R. E. et al. Antitumour effects of EMAP II against pancreatic cancer through inhibition of fibronectin-dependent proliferation. Cancer Biol. Ther. 9, 632–639 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Awasthi, N., Schwarz, M. A. & Schwarz, R. E. Enhancing cytotoxic agent activity in experimental pancreatic cancer through EMAP II combination therapy. Cancer Chemother. Pharmacol. 26 Nov 2010 (doi: 10.1007/s00280-010-1514-7).

  100. Reznikov, A. G., Chaykovskaya, L. V., Polyakova, L. I. & Kornelyuk, A. I. Antitumour effect of endothelial monocyte-activating polypeptide-II on human prostate adenocarcinoma in mouse xenograft model. Exp. Oncol. 29, 267–271 (2007).

    CAS  PubMed  Google Scholar 

  101. Silvera, D., Formenti, S. C. & Schneider, R. J. Translational control in cancer. Nature Rev. Cancer 10, 254–266 (2010).

    Article  CAS  Google Scholar 

  102. Antonellis, A. et al. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72, 1293–1299 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Jordanova, A. et al. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nature Genet. 38, 197–202 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Corti, O. et al. The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum. Mol. Genet. 12, 1427–1437 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Ko, H. S. et al. Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J. Neurosci. 25, 7968–7978 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Feinstein, M. et al. Pelizaeus-Merzbacher-like disease caused by AIMP1/p43 homozygous mutation. Am. J. Hum. Genet. 87, 820–828 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhu, X. et al. MSC p43 required for axonal development in motor neurons. Proc. Natl Acad. Sci. USA 106, 15944–15949 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. ' t Hart, L. M. et al. Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene. Diabetes 54, 1892–1895 (2005).

    Article  CAS  Google Scholar 

  109. Ohkubo, K. et al. Mitochondrial gene mutations in the tRNALeu(UUR) region and diabetes: prevalence and clinical phenotypes in Japan. Clin. Chem. 47, 1641–1648 (2001).

    CAS  PubMed  Google Scholar 

  110. Zhou, W. et al. Inactivation of LARS2, located at the commonly deleted region 3p21.3, by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma. Acta Biochim. Biophys. Sin (Shanghai) 41, 54–62 (2009).

    Article  CAS  Google Scholar 

  111. Martinis, S. A. & Boniecki, M. T. The balance between pre- and post-transfer editing in tRNA synthetases. FEBS Lett. 584, 455–459 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. McLennan, A. G. Dinucleoside polyphosphates-friend or foe? Pharmacol. Ther. 87, 73–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Nechushtan, H., Kim, S., Kay, G. & Razin, E. Chapter 1: the physiological role of lysyl tRNA synthetase in the immune system. Adv. Immunol. 103, 1–27 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Lee, Y. N., Nechushtan, H., Figov, N. & Razin, E. The function of lysyl-tRNA synthetase and Ap4A as signalling regulators of MITF activity in FcɛRI-activated mast cells. Immunity 20, 145–151 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Medicinal Bioconvergence Research Center, Seoul National University, 151-742, Seoul, Republic of Korea

    Sunghoon Kim

  2. School of Interdisciplinary Bioscience and Bioengineering and department of Chemical Engineering, Pohang University of Science and Technology, 790-784, Pohang, Republic of Korea

    Sungyong You & Daehee Hwang

  3. Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, 790-784, Pohang, Republic of Korea

    Daehee Hwang

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  1. Sunghoon Kim
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Supplementary information

Supplementary information S1 (text)

Selection of cancer-associated genes (PDF 66 kb)

Supplementary information S2 (table)

3501 Cancer-associated genes (CAGs) and interactors of ARSs and AIMPs (XLS 953 kb)

Supplementary information S3 (text)

Identification of the CAGs directly interacting with ARSs and AIMPs (PDF 97 kb)

Supplementary information S4 (table)

644 interactions of ARSs and AIMPs (XLS 135 kb)

Supplementary information S5 (table)

Non-cancer-associated genes (non-CAGs) (XLS 2805 kb)

Supplementary information S6 (table)

40 cancer-associated mRNA datasets (XLS 21 kb)

Supplementary information S7 (text)

Similarity comparison in the expression profiles of ARSN, CAGs and non-CAGs (PDF 130 kb)

Supplementary information S8 (figure)

Copy number variations obtained from Tumorscape (PDF 95 kb)

Supplementary information S9 (table)

Phsphorylated sites of ARS and AIMPs (XLS 42 kb)

Supplementary information S10 (text)

Cancer association scores of ARSs and AIMPs in the network (PDF 95 kb)

Supplementary information S11 (text)

Association of ARSs and AIMPs with biological processes and cancer types (PDF 93 kb)

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FURTHER INFORMATION

Sunghoon Kim's homepage

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CanGEM

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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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