Biologically Active Fragment of a Human tRNA Synthetase Inhibits Fluid Shear Stress-Activated Responses of Endothelial Cells

Human tryptophanyl-tRNA synthetase (TrpRS) is active in translation and angiogenesis. In particular, an N-terminally truncated fragment, T2-TrpRS, that is closely related to a natural splice variant is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in several in vivo...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2003-12, Vol.100 (25), p.14903-14907
Hauptverfasser: Tzima, E., Reader, J. S., Irani-Tehrani, M., Ewalt, K. L., Schwartz, M. A., Schimmel, P.
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Tzima, E.
Reader, J. S.
Irani-Tehrani, M.
Ewalt, K. L.
Schwartz, M. A.
Schimmel, P.
description Human tryptophanyl-tRNA synthetase (TrpRS) is active in translation and angiogenesis. In particular, an N-terminally truncated fragment, T2-TrpRS, that is closely related to a natural splice variant is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in several in vivo models. In contrast, full-length native TrpRS is inactive in the same models. However, vascular endothelial growth factor stimulation is only one of many physiological and pathophysiological stimuli to which the vascular endothelium responds. To investigate more broadly the role of T2-TrpRS in vascular homeostasis and pathophysiology, the effect of T2-TrpRS on well characterized endothelial cell (EC) responses to flow-induced fluid shear stress was studied. T2-TrpRS inhibited activation by flow of protein kinase B (Akt), extracellular signal-regulated kinase 1/2, and EC NO synthase and prevented transcription of several shear stress-responsive genes. In addition, T2-TrpRS interfered with the unique ability of ECs to align in the direction of fluid flow. In all of these assays, native TrpRS was inactive, demonstrating that angiogenesis-related activity requires fragment production. These results demonstrate that T2-TrpRS can regulate extracellular signal-activated protein kinase, Akt, and EC NO synthase activation pathways that are associated with angio-genesis, cytoskeletal reorganization, and shear stress-responsive gene expression. Thus, this biological fragment of TrpRS may have a role in the maintenance of vascular homeostasis.
doi_str_mv 10.1073/pnas.2436330100
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T2-TrpRS inhibited activation by flow of protein kinase B (Akt), extracellular signal-regulated kinase 1/2, and EC NO synthase and prevented transcription of several shear stress-responsive genes. In addition, T2-TrpRS interfered with the unique ability of ECs to align in the direction of fluid flow. In all of these assays, native TrpRS was inactive, demonstrating that angiogenesis-related activity requires fragment production. These results demonstrate that T2-TrpRS can regulate extracellular signal-activated protein kinase, Akt, and EC NO synthase activation pathways that are associated with angio-genesis, cytoskeletal reorganization, and shear stress-responsive gene expression. 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S.</creatorcontrib><creatorcontrib>Irani-Tehrani, M.</creatorcontrib><creatorcontrib>Ewalt, K. L.</creatorcontrib><creatorcontrib>Schwartz, M. A.</creatorcontrib><creatorcontrib>Schimmel, P.</creatorcontrib><title>Biologically Active Fragment of a Human tRNA Synthetase Inhibits Fluid Shear Stress-Activated Responses of Endothelial Cells</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Human tryptophanyl-tRNA synthetase (TrpRS) is active in translation and angiogenesis. In particular, an N-terminally truncated fragment, T2-TrpRS, that is closely related to a natural splice variant is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in several in vivo models. In contrast, full-length native TrpRS is inactive in the same models. 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subjects Actins
Amino Acyl-tRNA Synthetases - metabolism
Angiogenesis
Animals
Biological Sciences
Blood vessels
Cattle
Cellular biology
Cytoskeleton - metabolism
Endothelial cells
Endothelial growth factors
Endothelium, Vascular - metabolism
Gene expression regulation
Genetic Vectors
Humans
Luciferases - metabolism
Microscopy, Fluorescence
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - metabolism
Neovascularization, Pathologic
Nitric Oxide Synthase - metabolism
Phosphorylation
Physiological regulation
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Ribonucleic acid
RNA
Shear stress
Signal Transduction
Stress fibers
Stress, Mechanical
Temperature
Time Factors
Transcription, Genetic
title Biologically Active Fragment of a Human tRNA Synthetase Inhibits Fluid Shear Stress-Activated Responses of Endothelial Cells
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