title: Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis.
abstract: Aminoacyl-tRNA synthetases classically regulate protein synthesis but some also engage in alternative signaling functions related to immune responses and angiogenesis. Threonyl-tRNA synthetase (TARS) is an autoantigen in the autoimmune disorder myositis, and borrelidin, a potent inhibitor of TARS, inhibits angiogenesis. We explored a mechanistic link between these findings by testing whether TARS directly affects angiogenesis through inflammatory mediators. When human vascular endothelial cells were exposed to tumor necrosis factor-α (TNF-α) or vascular endothelial growth factor (VEGF), TARS was secreted into the cell media. Furthermore, exogenous TARS stimulated endothelial cell migration and angiogenesis in both in vitro and in vivo assays. The borrelidin derivative BC194 reduced the angiogenic effect of both VEGF and TARS, but not a borrelidin-resistant TARS mutant. Our findings reveal a previously undiscovered function for TARS as an angiogenic, pro-migratory extracellular signaling molecule. TARS thus provides a potential target for detecting or interdicting disease-related inflammatory or angiogenic responses.
authors: Department of Pharmacology, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
authors: Tamara F
authors: TF
authors: Williams
authors: Adam C
authors: AC
authors: Mirando
authors: Barrie
authors: B
authors: Wilkinson
authors: Christopher S
authors: CS
authors: Francklyn
authors: Karen M
authors: KM
authors: Lounsbury
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D010446:Peptide Fragments / Q000494:pharmacology; D013914:Threonine-tRNA Ligase / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D056811:Unfolded Protein Response; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D018836:Inflammation Mediators; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013914:Threonine-tRNA Ligase