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. 2014 Dec 19;15(12):23725–23748. doi: 10.3390/ijms151223725

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© 2014 by the authors; licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).

PMC Copyright notice

Mechanisms of angiogenesis by intracellularly acting ARS. (1) seryl-tRNA synthetase (SARS) is transported into the nucleus via a canonical nuclear localization sequence (NLS) sequence and binds to the vascular endothelial growth factor A gene (vegfaa) promoter. The binding of SARS inhibits c-Myc-mediated expression of vascular endothelial growth factor A (VEGFA) through modification of vegfaa epigenetics. This effect is angiostatic; (2) glutamyl-prolyl-tRNA synthetase (EPRS) is phosphorylated upon treatment of the cell with IFNγ, releasing it from the multisynthetase complex (MSC). Phospho-EPRS binds with L13a, GAPDH, and NSAP1 to form the interferon-γ-activated inhibitor of translation (GAIT) complex. This complex then binds to mRNA containing stem-loop, 3' UTR GAIT elements via EPRS WHEP domains, thereby blocking their translation. As VEGFA contains a GAIT element, this effect is angiostatic.