Disease relevance of GARS

• Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V [1].
• Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal peripheral neuropathies inherited in an autosomal dominant fashion [1].
• Expression of the cDNA in Escherichia coli yielded a protein of expected size that reacted with the autoantibodies and was active as glycyl-tRNA synthetase [2].
• Two identical cDNAs encoding human glycyl-tRNA synthetase were isolated from K562 and HEL cell lambda gt11 libraries by screening with "anti-EJ" autoantibodies from a patient with dermatomyositis, previously shown to specifically inhibit this enzyme [2].
• Primary structure and functional expression of human Glycyl-tRNA synthetase, an autoantigen in myositis [2].

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

• MAPKs cascades were established to be a major signal pathway for driving tumor cell metastasis, which are mediated by PKC, TGF-beta/Smad and integrin-mediated signaling [12].

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

• Using these antibodies on western blots of Chinese hamster ovary (CHO) cells transfected with the human GARS-AIRS-GART gene, we show that this gene encodes not only the trifunctional protein of 110 kDa, but also a monofunctional GARS protein of 50 kDa [16].
• We screened 100 patients with inherited and sporadic lower motor neuron degeneration and identified three novel missense mutations in the glycyl-tRNA synthetase (GARS) gene [17].
• Finally, we detected endogenous GARS-associated granules in the neurite projections of cultured neurons and in the peripheral nerve axons of normal human tissue [18].
• One mutation was in the anticodon binding domain and associated with onset in early childhood and predominant involvement of the lower limbs, thus extending the phenotype associated with GARS mutations [17].
• Peptide expression influenced by human chromosome 21 was examined by comparing two-dimensional electrophoretograms of a human-hamster hybrid cell containing human chromosome 21 with its parent hamster cell and a revertant of the hybrid which had segregated the chromosome 21 genes for SOD-1, GARS, and a cytotoxic cell-surface antigen [19].

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

• In this study, we demonstrate that SHP represses transforming growth factor-beta (TGF-beta)-induced gene expression through a direct interaction with Smad, a transducer of TGF-beta signaling [29].
• We demonstrated in vivo that Smad1 signaling is low in androgen-regulated growth of prostate cancer, is activated after castration, and also is decreased in hormone-independent tumors [30].
• The primary structure of the gene encoding Bombyx mori glycyl-tRNA synthetase was determined by sequence analysis of one cDNA and two genomic clones [31].
• Immunoblotting and immunocytochemistry were applied to evaluate phosphorylated Smad and E-cadherin expression in relation to mTOR inhibition and TGF-beta1 exposure [32].
• CD105 expression was analyzed on resting and activated human CD4(+) T cells by flow cytometry, western blot, immunoprecipitation, proliferation and SMAD-responsive reporter gene assays [33].

References