Activation of Angiogenic Signaling Pathways by Two Human tRNA Synthetases

Abstract

Aminoacyl-tRNA synthetases establish the rules of the genetic code by joining amino acids to tRNAs that bear the anticodon triplets corresponding to the attached amino acids. The enzymes are thought to be among the earliest proteins to appear, in the transition from a putative RNA world to the theater of proteins. Over their long evolution, the enzymes have acquired additional functions that typically require specialized insertions or domain fusions. Recently, fragments of the closely related human tyrosyl- and tryptophanyl-tRNA synthetases were discovered to be active in angiogenesis signaling pathways. One synthetase fragment has proangiogenic activity, while the other is antiangiogenic. Activity was demonstrated in cell-based assays in vitro and in vivo in the chick embryo, and in the neonatal and adult mouse. The full-length, native enzymes are inactive in these same assays. Activation of angiogenesis activity requires fragment production from the native enzymes by protease cleavage or by translation of alternatively spliced pre-mRNA. Thus, these tRNA synthetases link translation to a major cell-signaling pathway in mammalian cells. The results with animals suggest that therapeutic applications are possible with these tRNA synthetases.

Effect of Mini‐Tyrosyl‐tRNA Synthetase/Mini‐Tryptophanyl‐tRNA Synthetase on Angiogenesis in Rhesus Monkeys after Acute Myocardial Infarction

“…One potential new approach is angiogenic gene transfer. Because of its potential angiogenic benefits, mini-TyrRS/ mini-TrpRS has received increasing attention [6][7][8][9][10]. In this study, we investigated the effect of mini-TyrRS/mini-TrpRS in ischemic angiogenesis in rhesus monkeys with AMI.…”

“…Minityrosyl-tRNA synthetase (mini-TyrRS) has recently been shown to stimulate neutrophil activation and chemotaxis in vitro and is angiogenic in endothelial cell cultures, chick chorioallantoic membranes (CAM), and mouse matrigel implants [6][7][8][9]. Like CXC chemokines, such as IL-8, mini-TyrRS has an ELR motif (Glu-Leu-Arg) that confers its chemokine and angiogenic activities.…”

“…In mammalian cells, TrpRS is activated for anti-angiogenic signaling by proteolysis or alternative splicing to give the natural isoform mini-TrpRS. Mini-TrpRS inhibits the development of new vessels without affecting the pre-established vasculature [8,9]. Regions within mini-TrpRS that contribute to angiostatic activity have been proposed [10][11][12][13], and the anti-angiogenic activity of mini-TrpRS has also been demonstrated in cell-based assays in vitro and also in vivo in the chick CAM and mouse matrigel assays [10][11][12][13].…”

Biologically active fragment of a human tRNA synthetase inhibits fluid shear stress-activated responses of endothelial cells

“…The role of T2-TrpRS in signaling events that control morphology and gene expression of ECs is not surprising considering the similarity between TrpRS expression and expression of a number of other genes involved in signal transduction and cell adhesion pathways (7). Although the receptor mediating T2-TrpRS cell signaling is unknown, the fact that T2-TrpRS inhibited shear stress responses as well as vascular endothelial growth factor-stimulated signaling in cultured ECs suggests a more general mechanism in which T2-TrpRS specifically inhibits EC activation, which may explain the observed antiangiogenic activity in three separate in vivo angiogenesis models (5,6).…”

Small interfering RNA knockdown of mini-TyrRS and mini-TrpRS effects angiogenesis in human umbilical vein endothelial cells in hypoxic culture

“…This demonstration established a link between protein synthesis and signal transduction. At the same time, mammalian TyrRS and TrpRS have also been shown to regulate angiogenesis (Wakasugi and Schimmel 1999b;Wakasugi et al 2002a, b;Otani et al 2002;Ewalt and Schimmel 2002;Ibba 2000).…”