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Gene Review

GARS  -  glycyl-tRNA synthetase

Homo sapiens

Synonyms: AP-4-A synthetase, CMT2D, DSMAV, Diadenosine tetraphosphate synthetase, GlyRS, ...
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Disease relevance of GARS


Psychiatry related information on GARS

  • Hierarchical multiple regression analysis was used to study the impact of depressive symptoms (as assessed with the Hospital Anxiety and Depression Scale; HADS) on disability (as assessed with the Groningen Activity Restriction Scale; GARS) after the injury while adjusting for several covariates [3].
  • Bone morphogenetic protein (BMP) family, SMAD signaling and Id helix-loop-helix proteins in the vasculature: the continuous mystery of BMPs pleotropic effects [4].
  • Given that a nuclear localization is required to regulate the transcription of TGF-beta target genes to afford neuroprotection, the ectopic localization of phosphorylated Smad2 suggests a defect in the Smad-mediated signaling pathway of TGF-beta in Alzheimer's disease and consequent loss of neuroprotective function [5].
  • The feeding mechanism of gars (Ginglymodi : Lepisosteidae) is characterized by cranial elevation and lower jaw rotation but minimal cranial kinesis [6].

High impact information on GARS

  • Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish [7].
  • Tissue homeostasis in mammals relies on powerful cytostatic and differentiation signals delivered by the cytokine TGFbeta and relayed within the cell via the activation of Smad transcription factors [8].
  • Recent cellular, biochemical, and structural studies have revealed significant insight into the mechanisms of the activation of TGF-beta receptors through ligand binding, the activation of Smad proteins through phosphorylation, the transcriptional regulation of target gene expression, and the control of Smad protein activity and degradation [9].
  • Upon phosphorylation by the receptors, Smad complexes translocate into the nucleus, where they cooperate with sequence-specific transcription factors to regulate gene expression [10].
  • Members of the transforming growth factor-beta (TGF-beta) family bind to type II and type I serine/threonine kinase receptors, which initiate intracellular signals through activation of Smad proteins [11].

Chemical compound and disease context of GARS


Biological context of GARS

  • Awareness of these overlapping clinical phenotypes associated with mutations in GARS will facilitate identification of this disorder in additional families and direct future research toward better understanding of its pathogenesis [13].
  • Linkage to chromosome 7p15 and the presence of disease-associated heterozygous GARS mutations have been identified in patients from each of the five studied families [13].
  • Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V [1].
  • Potential candidate genes are multiple T-cell gamma receptor genes which map to the same cytogenetic interval as CMT2D neuropathy [14].
  • Human glycyl-tRNA synthetase. Wide divergence of primary structure from bacterial counterpart and species-specific aminoacylation [15].

Anatomical context of GARS


Associations of GARS with chemical compounds

  • The human glycine tRNA synthetase gene (GlyRS) has been cloned and sequenced [20].
  • Bacterial extract containing the fusion protein catalyses the aminoacylation of bovine tRNA with [14C]-gly at 10-fold increased level above normal bacterial extract and confirms that the cDNA encodes human GlyRS [20].
  • In humans, the second, third and fifth steps of de novo purine biosynthesis are catalyzed by a trifunctional protein with glycinamide ribonucleotide synthetase (GARS), aminoimidazole ribonucleotide synthetase (AIRS) and glycinamide ribonucleotide formyltransferase (GART) enzymatic activities [16].
  • Next, whether oltipraz inhibits TGFbeta1-mediated Smads activation or Smad-mediated PAI-1 induction was determined in L929 fibroblasts [21].
  • Activins bind specific type II receptor serine kinases (ActRII or IIB) to promote the recruitment and phosphorylation of the type I receptor serine kinase, ALK4 (refs 7-9), which then regulates gene expression by activating Smad proteins [22].

Physical interactions of GARS

  • However, in presence of TSA, TGF-beta fails to induce Sp1 levels, its interaction with Smad complex and Sp1 binding site in COL1A2 promoter [23].

Regulatory relationships of GARS

  • Results further reveal that there is no significant alteration in Smad activation and function in presence of TSA suggesting suppression of TGF-beta-induced collagen synthesis is not due to impaired Smad signaling [23].
  • However, introduction of Smad1 into lymphocytes made the cells competent to regulate MSX2 mRNA after BMP4 treatment [24].
  • Smad1 siRNA transfection inhibited the upregulation of ID protein [25].
  • We determined the presence and functionality of BMPR1A by examining BMP-induced phosphorylation and nuclear translocation of SMAD1; transcriptional activity via a BMP-specific luciferase reporter; and growth characteristics by cell cycle analysis, cell growth, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide metabolic assays [26].
  • Bioassays revealed that FSH enhances BMP-induced SMAD1/5/8 phosphorylation and cellular DNA synthesis induced by BMP6 and BMP7 [27].

Other interactions of GARS

  • The expression of both the GARS and GARS-AIRS-GART proteins are regulated during development of the human cerebellum, while the expression of FGARAT appears to be constitutive [16].
  • Collectively, these results suggest that TSA-mediated suppression of Smad-dependent TGF-beta-induced collagen synthesis is due to suppression of Sp1 activity in skin fibroblasts [23].
  • GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription [25].
  • We also determined the expression of BMPR1A, BMP ligands, and phospho-SMAD1 in primary human colon cancer specimens [26].
  • Furthermore, the TNF-alpha-induced loss of BMPR-IB was found to ablate BMP-2-stimulated bone cell functions, including phosphorylation of Smad1/5/8, alkaline phosphatase activity and osteocalcin expression [28].

Analytical, diagnostic and therapeutic context of GARS


  1. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Antonellis, A., Ellsworth, R.E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L.T., Sivakumar, K., Ionasescu, V., Funalot, B., Vance, J.M., Goldfarb, L.G., Fischbeck, K.H., Green, E.D. Am. J. Hum. Genet. (2003) [Pubmed]
  2. Primary structure and functional expression of human Glycyl-tRNA synthetase, an autoantigen in myositis. Ge, Q., Trieu, E.P., Targoff, I.N. J. Biol. Chem. (1994) [Pubmed]
  3. The role of depressive symptoms in recovery from injuries to the extremities in older persons. A prospective study. Kempen, G.I., Sanderman, R., Scaf-Klomp, W., Ormel, J. International journal of geriatric psychiatry. (2003) [Pubmed]
  4. Bone morphogenetic protein (BMP) family, SMAD signaling and Id helix-loop-helix proteins in the vasculature: the continuous mystery of BMPs pleotropic effects. Abe, J. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  5. Ectopic expression of phospho-Smad2 in Alzheimer's disease: Uncoupling of the transforming growth factor-beta pathway? Lee, H.G., Ueda, M., Zhu, X., Perry, G., Smith, M.A. J. Neurosci. Res. (2006) [Pubmed]
  6. Comparative and developmental functional morphology of the jaws of living and fossil gars (Actinopterygii: Lepisosteidae). Kammerer, C.F., Grande, L., Westneat, M.W. J. Morphol. (2006) [Pubmed]
  7. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Lin, X., Duan, X., Liang, Y.Y., Su, Y., Wrighton, K.H., Long, J., Hu, M., Davis, C.M., Wang, J., Brunicardi, F.C., Shi, Y., Chen, Y.G., Meng, A., Feng, X.H. Cell (2006) [Pubmed]
  8. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. He, W., Dorn, D.C., Erdjument-Bromage, H., Tempst, P., Moore, M.A., Massagué, J. Cell (2006) [Pubmed]
  9. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Shi, Y., Massagué, J. Cell (2003) [Pubmed]
  10. Specificity and versatility in tgf-beta signaling through Smads. Feng, X.H., Derynck, R. Annu. Rev. Cell Dev. Biol. (2005) [Pubmed]
  11. TGF-beta signaling by Smad proteins. Miyazono, K., ten Dijke, P., Heldin, C.H. Adv. Immunol. (2000) [Pubmed]
  12. The signaling mechanism of ROS in tumor progression. Wu, W.S. Cancer Metastasis Rev. (2006) [Pubmed]
  13. Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Sivakumar, K., Kyriakides, T., Puls, I., Nicholson, G.A., Funalot, B., Antonellis, A., Sambuughin, N., Christodoulou, K., Beggs, J.L., Zamba-Papanicolaou, E., Ionasescu, V., Dalakas, M.C., Green, E.D., Fischbeck, K.H., Goldfarb, L.G. Brain (2005) [Pubmed]
  14. Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Ionasescu, V., Searby, C., Sheffield, V.C., Roklina, T., Nishimura, D., Ionasescu, R. Hum. Mol. Genet. (1996) [Pubmed]
  15. Human glycyl-tRNA synthetase. Wide divergence of primary structure from bacterial counterpart and species-specific aminoacylation. Shiba, K., Schimmel, P., Motegi, H., Noda, T. J. Biol. Chem. (1994) [Pubmed]
  16. The human GARS-AIRS-GART gene encodes two proteins which are differentially expressed during human brain development and temporally overexpressed in cerebellum of individuals with Down syndrome. Brodsky, G., Barnes, T., Bleskan, J., Becker, L., Cox, M., Patterson, D. Hum. Mol. Genet. (1997) [Pubmed]
  17. Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene. James, P.A., Cader, M.Z., Muntoni, F., Childs, A.M., Crow, Y.J., Talbot, K. Neurology (2006) [Pubmed]
  18. Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. Antonellis, A., Lee-Lin, S.Q., Wasterlain, A., Leo, P., Quezado, M., Goldfarb, L.G., Myung, K., Burgess, S., Fischbeck, K.H., Green, E.D. J. Neurosci. (2006) [Pubmed]
  19. Two-dimensional electrophoresis of peptides from human-CHO cell hybrids containing human chromosome 21. Scoggin, C.H., Paul, S., Miller, Y.E., Patterson, D. Somatic Cell Genet. (1983) [Pubmed]
  20. Cloning, sequencing and bacterial expression of human glycine tRNA synthetase. Williams, J., Osvath, S., Khong, T.F., Pearse, M., Power, D. Nucleic Acids Res. (1995) [Pubmed]
  21. Inhibition of TGFbeta1-mediated PAI-1 induction by oltipraz through selective interruption of Smad 3 activation. Cho, I.J., Kim, S.H., Kim, S.G. Cytokine (2006) [Pubmed]
  22. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Lewis, K.A., Gray, P.C., Blount, A.L., MacConell, L.A., Wiater, E., Bilezikjian, L.M., Vale, W. Nature (2000) [Pubmed]
  23. Trichostatin A blocks TGF-beta-induced collagen gene expression in skin fibroblasts: Involvement of Sp1. Ghosh, A.K., Mori, Y., Dowling, E., Varga, J. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  24. Dysregulation of the BMP-p38 MAPK signaling pathway in cells from patients with fibrodysplasia ossificans progressiva (FOP). Fiori, J.L., Billings, P.C., de la Peña, L.S., Kaplan, F.S., Shore, E.M. J. Bone Miner. Res. (2006) [Pubmed]
  25. Upregulation of ID protein by growth and differentiation factor 5 (GDF5) through a smad-dependent and MAPK-independent pathway in HUVSMC. Chen, X., Zankl, A., Niroomand, F., Liu, Z., Katus, H.A., Jahn, L., Tiefenbacher, C. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  26. Bone morphogenetic protein signaling and growth suppression in colon cancer. Beck, S.E., Jung, B.H., Fiorino, A., Gomez, J., Rosario, E.D., Cabrera, B.L., Huang, S.C., Chow, J.Y., Carethers, J.M. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  27. Mutual regulation of follicle-stimulating hormone signaling and bone morphogenetic protein system in human granulosa cells. Miyoshi, T., Otsuka, F., Suzuki, J., Takeda, M., Inagaki, K., Kano, Y., Otani, H., Mimura, Y., Ogura, T., Makino, H. Biol. Reprod. (2006) [Pubmed]
  28. Bone morphogenetic protein receptors and bone morphogenetic protein signaling are controlled by tumor necrosis factor-alpha in human bone cells. Singhatanadgit, W., Salih, V., Olsen, I. Int. J. Biochem. Cell Biol. (2006) [Pubmed]
  29. Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Transforming Growth Factor-beta Signaling by Repressing SMAD3 Transactivation. Suh, J.H., Huang, J., Park, Y.Y., Seong, H.A., Kim, D., Shong, M., Ha, H., Lee, I.K., Lee, K., Wang, L., Choi, H.S. J. Biol. Chem. (2006) [Pubmed]
  30. Control of prostate cell growth: BMP antagonizes androgen mitogenic activity with incorporation of MAPK signals in Smad1. Qiu, T., Grizzle, W.E., Oelschlager, D.K., Shen, X., Cao, X. EMBO J. (2007) [Pubmed]
  31. Primary structure of the gene for glycyl-tRNA synthetase from Bombyx mori. Nada, S., Chang, P.K., Dignam, J.D. J. Biol. Chem. (1993) [Pubmed]
  32. Mammalian target of rapamycin and 3-phosphatidylinositol 3-kinase pathway inhibition enhances growth inhibition of transforming growth factor-beta1 in prostate cancer cells. van der Poel, H.G. J. Urol. (2004) [Pubmed]
  33. TGF-{beta} signaling of human T cells is modulated by the ancillary TGF-{beta} receptor endoglin. Schmidt-Weber, C.B., Letarte, M., Kunzmann, S., Rückert, B., Bernabéu, C., Blaser, K. Int. Immunol. (2005) [Pubmed]
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