VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function.
A natural fragment of an enzyme that catalyzes the first step of protein synthesis-human tryptophanyl-tRNA synthetase (T2-TrpRS) has potent anti-angiogenic activity. A cellular receptor through which T2-TrpRS exerts its anti-angiogenic activity has not previously been identified. Here T2-TrpRS was shown to bind at intercellular junctions of endothelial cells (ECs). Using genetic knock-outs, binding was established to depend on VE-cadherin, a calcium-dependent adhesion molecule, which is selectively expressed in ECs, concentrated at adherens junctions, and is essential for normal vascular development. In contrast, T2-TrpRS binding to EC junctions was not dependent on platelet endothelial cell adhesion molecule type-1, another adhesion molecule found at EC junctions. Pull-down assays confirmed direct complex formation between T2-TrpRS and VE-cadherin. Binding of T2-TrpRS inhibited VEGF-induced ERK activation and EC migration. Thus, a VE-cadherin-dependent pathway is proposed to link T2-TrpRS to inhibition of new blood vessel formation.
Tzima
Eleni
E
Skaggs Institute for Chemical Biology, Department of Chemistry and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA. etzima@scripps.edu
Reader
John S
JS
Irani-Tehrani
Mohamad
M
Ewalt
Karla L
KL
Schwartz
Martin A
MA
Schimmel
Paul
P
D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD; D001011:Aorta / Q000166:cytology; D015153:Blotting, Western; D015820:Cadherins / Q000502:physiology*; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017629:Gap Junctions; D049452:Green Fluorescent Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D014369:Tryptophan-tRNA Ligase / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099152:Cadherin 5
D000604:Amino Acyl-tRNA Synthetases; D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D015820:Cadherins; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D049452:Green Fluorescent Proteins; D011994:Recombinant Proteins; D014369:Tryptophan-tRNA Ligase; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5