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 |
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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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S. ; Irani-Tehrani, M. ; Ewalt, K. L. ; Schwartz, M. A. ; Schimmel, P.</creator><creatorcontrib>Tzima, E. ; Reader, J. S. ; Irani-Tehrani, M. ; Ewalt, K. L. ; Schwartz, M. A. ; Schimmel, P.</creatorcontrib><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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2436330100</identifier><identifier>PMID: 14630953</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2003-12, Vol.100 (25), p.14903-14907</ispartof><rights>Copyright 1993-2003 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Dec 9, 2003</rights><rights>Copyright © 2003, The National Academy of Sciences 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-f71b2bc769a2a27825936145cd9dbe01374a1d951d609aaab4451ddef43f04af3</citedby><cites>FETCH-LOGICAL-c526t-f71b2bc769a2a27825936145cd9dbe01374a1d951d609aaab4451ddef43f04af3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/100/25.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3148533$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3148533$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,728,781,785,804,886,27929,27930,53796,53798,58022,58255</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14630953$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tzima, E.</creatorcontrib><creatorcontrib>Reader, J. 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. 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.</description><subject>Actins</subject><subject>Amino Acyl-tRNA Synthetases - metabolism</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Blood vessels</subject><subject>Cattle</subject><subject>Cellular biology</subject><subject>Cytoskeleton - metabolism</subject><subject>Endothelial cells</subject><subject>Endothelial growth factors</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Gene expression regulation</subject><subject>Genetic Vectors</subject><subject>Humans</subject><subject>Luciferases - metabolism</subject><subject>Microscopy, Fluorescence</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Neovascularization, Pathologic</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Phosphorylation</subject><subject>Physiological regulation</subject><subject>Protein Structure, Tertiary</subject><subject>Protein-Serine-Threonine Kinases</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Shear stress</subject><subject>Signal Transduction</subject><subject>Stress fibers</subject><subject>Stress, Mechanical</subject><subject>Temperature</subject><subject>Time Factors</subject><subject>Transcription, Genetic</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc-LEzEUxwdR3Lp69iISPAgeZvflx_zIwUMtW3dhUdjqObyZybQp6aQmmcWCf7ypLVv1shDIg3y-3_devln2msIFhYpfbgcMF0zwknOgAE-yCQVJ81JIeJpNAFiV14KJs-xFCGsAkEUNz7MzKkqeaj7Jfn0yzrqladHaHZm20dxrMve43OghEtcTJNfjBgcS775MyWI3xJWOGDS5GVamMTGQuR1NRxYrjZ4sotch5H9sMOqO3OmwdUPQYW91NXQuya1BS2ba2vAye9ajDfrV8T7Pvs-vvs2u89uvn29m09u8LVgZ876iDWvaqpTIkFU1KyQvqSjaTnaNBsorgbSTBe1KkIjYCJHqTveC9yCw5-fZx4Pvdmw2umvTah6t2nqzQb9TDo3692UwK7V094pJWReQ9O-Peu9-jDpEtTGhTRvgoN0YVJWGoRWVj4JUspILWSfw3X_g2o1-SJ-gGFBWl-kk6PIAtd6F4HX_MDEFtY9f7eNXp_iT4u3fi574Y94JIEdgrzzZgWJFoiTskQ-PIKofrY36Z0zsmwO7DtH5B5hTUadm_De2hc7k</recordid><startdate>20031209</startdate><enddate>20031209</enddate><creator>Tzima, E.</creator><creator>Reader, J. 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S.</au><au>Irani-Tehrani, M.</au><au>Ewalt, K. L.</au><au>Schwartz, M. A.</au><au>Schimmel, P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biologically Active Fragment of a Human tRNA Synthetase Inhibits Fluid Shear Stress-Activated Responses of Endothelial Cells</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2003-12-09</date><risdate>2003</risdate><volume>100</volume><issue>25</issue><spage>14903</spage><epage>14907</epage><pages>14903-14907</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>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. 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>14630953</pmid><doi>10.1073/pnas.2436330100</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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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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