HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: fj.07-9973comv1 22/5/1597    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Greenberg, Y. Articles by Tzima, E. Search for Related Content PubMed PubMed Citation Articles by Greenberg, Y. Articles by Tzima, E.

The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells

Y. Greenberg^*, M. King^*, W. B. Kiosses, K. Ewalt, X. Yang, P. Schimmel, J. S. Reader^, and E. Tzima^*,,1

^* Department of Cell and Molecular Physiology,

Department of Molecular Biology, The Scripps Research Institute,

Department of Medicine, and

Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina

¹Correspondence: Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, 103 Mason Farm Rd., Chapel Hill, NC 27599-7545. E-mail: etzima{at}med.unc.edu

Aminoacyl tRNA synthetases—enzymes that catalyze the first step of protein synthesis—in mammalian cells are now known to have expanded functions, including activities in signal transduction pathways, such as those for angiogenesis and inflammation. The native synthetases themselves are procytokines, having no signal transduction activities. After alternative splicing or natural proteolysis, specific fragments that are potent cytokines and that interact with specific receptors on cell surfaces are released. In this manner, a natural fragment of human tyrosyl tRNA synthetase (TyrRS), mini-TyrRS, has been shown to act as a proangiogenic cytokine. The mechanistic basis for the action of mini-TyrRS in angiogenesis has yet to be established. Here, we show that mini-TyrRS is exported from endothelial cells when they are treated with tumor necrosis factor-. Mini-TyrRS binds to vascular endothelial cells and activates an array of angiogenic signal transduction pathways. Mini-TyrRS-induced angiogenesis requires the activation of vascular endothelial growth factor receptor-2 (VEGFR2/Flk-1/KDR). Mini-TyrRS stimulates VEGFR2 phosphorylation in a VEGF-independent manner, suggesting VEGFR2 transactivation. Transactivation of VEGFR2 and downstream angiogenesis require an intact Glu-Leu-Arg (ELR) motif in mini-TyrRS, which is important for its cytokine activity. These studies therefore suggest a mechanism by which mini-TyrRS induces angiogenesis in endothelial cells and provide further insight into the role of mini-TyrRS as a link between translation and angiogenesis.—Greenberg, Y., King, M., Kiosses, W. B., Ewalt, K., Yang, X., Schimmel, P., Reader, J. S., and Tzima, E. The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells.

Key Words: angiogenesis • vascular endothelial growth factor receptor 2 • noncanonical