Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping

Kim, Sung Hoon; You, Sungyong; Hwang, Daehee

doi:10.1038/nrc3124

Cited by 248 publications

(277 citation statements)

References 111 publications

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“…These domain additions are not needed for catalysis, but rather to endow the synthetases with functions beyond translation. These functions are associated with secreted, extracellular forms and with nuclear forms that are active in many different cell-signaling pathways (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In addition, a recent study demonstrated that a novel domain, appended to SerRS at the time of the invertebrate to vertebrate transition, was essential for development of the closed vascular system (13).…”

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confidence: 99%

Regulated Capture by Exosomes of mRNAs for Cytoplasmic tRNA Synthetases

Wang

Zhou

et al. 2013

Journal of Biological Chemistry

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Background: Many tRNA synthetases (AARS) have extracellular and nuclear functions. Some of these functions might require the export of their mRNAs. Results: Packaging in exosomes of mRNAs for AARSs and a splice variant was demonstrated. Conclusion: Exosomes capture translation-competent AARS-derived mRNAs, which can be regulated by external stimuli. Significance: Exosomes are a source for extracellular distribution of AARS-derived RNA information.

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confidence: 99%

Regulated Capture by Exosomes of mRNAs for Cytoplasmic tRNA Synthetases

Wang

Zhou

et al. 2013

Journal of Biological Chemistry

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“…These expansions, often implemented with secreted forms, developed in evolution through the incorporation of novel domains and sequence motifs that bear no impact on the protein synthesis function. That these additions were added at precise time points in evolution and are tightly regulated suggests that they played a role in the development of higher organisms (7)(8)(9).…”

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confidence: 99%

Uncovering of a Short Internal Peptide Activates a tRNA Synthetase Procytokine

Lee

Zhang

Marshall

et al. 2012

Journal of Biological Chemistry

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Background: Many tRNA synthetases have acquired expanded functions unrelated to their canonical aminoacylation function. Results: Structural analysis in solution showed that a subtle conformational change causes pinpointed exposure of an evolutionarily acquired ELR tripeptide of human tyrosyl-tRNA synthetase, which activates its cytokine function. Conclusion:The exposure of ELR of TyrRS confers cytokine activity. Significance: The TyrRS design facilitates functional expansion while retaining its essential role in translation.In higher organisms, aminoacyl-tRNA synthetases developed receptor-mediated ex-translational functions that are activated by various natural mechanisms. Hydrogen-deuterium exchange combined with mass spectrometry and small-angle x-ray scattering showed that activation of the cytokine function of the 528-amino acid human tyrosyl-tRNA synthetase was associated with pinpointed uncovering of a miniature internal ELR tripeptide that triggers receptor signaling. The results reveal the structural simplicity of how the ex-translational function is implemented.Aminoacyl-tRNA synthetases are ancient enzymes that catalyze the first step of protein synthesis by attaching amino acids onto their cognate tRNAs (1). In addition, in higher organisms, aminoacyl-tRNA synthetases gained a variety of expanded functions in cell signaling pathways ranging from vascular to inflammatory pathways, among others (2-6). These expansions, often implemented with secreted forms, developed in evolution through the incorporation of novel domains and sequence motifs that bear no impact on the protein synthesis function. That these additions were added at precise time points in evolution and are tightly regulated suggests that they played a role in the development of higher organisms (7-9).Human tyrosyl-tRNA synthetase (TyrRS) 2 is a 528-amino acid procytokine composed of two domains connected by a long linker that spans ϳ20 amino acids (Fig. 1A). The 364-amino acid N-terminal part (mini-TyrRS) is the catalytic aminoacylation domain and is active without the C-terminal domain (CTD) (10,11). At the evolutionary stage of insects, an ELR tripeptide was incorporated into the mini-TyrRS domain and has been retained in higher organisms. The ELR motif is the recognition element within CXC chemokines such as interleukin-8, which mediates the innate immune response as well as angiogenesis (12,13). Simultaneously, the CTD, which is a structural and functional homolog of human endothelial monocyte-activating polypeptide II (EMAP II), was appended to TyrRS. Previous work established that mini-TyrRS and the CTD have distinct cytokine activities associated with hematological and inflammatory pathways, whereas full-length TyrRS is inactive as a cytokine (14,15). Thus, the novel activities are observed only when the two domains of secreted TyrRS are separated by natural proteolysis at the interdomain linker.The crystal structures of mini-TyrRS and the CTD have separately been determined (16,17). In the mini-TyrRS domain, the ELR motif is mask...

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“…ARSs ligate tRNAs with cognate amino acids, after which aminoacyl-tRNAs participate in translation, transporting precursor amino acids to the ribosome. 1 Although one tRNA is usually charged with only one of the 20 different amino acids, the human tRNAome is very complicated, and consists of more than 500 interspersed tRNA genes and 51 anticodon families. 2 Most tRNA groups incorporate isoacceptors that are charged with the same amino acid, but have different anticodons.…”

Section: Introductionmentioning

confidence: 99%

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

et al. 2018

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While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNALeu overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNALeu and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNALeu overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNALeu-binding protein. We suspected that the overexpression of free tRNALeu would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNALeu overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNALeu overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling.

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Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping

Cited by 248 publications

References 111 publications

Regulated Capture by Exosomes of mRNAs for Cytoplasmic tRNA Synthetases

Regulated Capture by Exosomes of mRNAs for Cytoplasmic tRNA Synthetases

Uncovering of a Short Internal Peptide Activates a tRNA Synthetase Procytokine

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

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