This project focuses on novel activities of two essential components of the translation apparatus in human cells. These components are aminoacyl tRNA synthetases. In their canonical role, aminoacyl tRNA synthetases catalyze aminoacylation of transfer RNAs in the first step of protein synthesis, and thereby establish the rules of the genetic code. Each of the 20 amino acids that make up proteins has a separate, distinct aminoacyl tRNA synthetase. In recent work we reported that one specific tRNA synthetase-for the amino acid tyrosine-could be split into two distinct cytokines. While the full-length protein is inactive, the two fragments are potent cytokines with distinct biological activities. The protein is secreted during apoptosis in cell culture and then can be cleaved by a protease such as leukocyte elastase. In further unpublished work, we found that the aforementioned fragments of this synthetase, and fragments of its close homolog that acts on the amino acid tryptophan, are active in angiogenesis or angiostasis. (Proteolysis or alternative splicing produces fragments of the latter enzyme.) The purpose of this project is to expand upon and further validate the initial observations of the activities of these fragments in angiogenesis or angiostasis, using several different assays for angiogenesis in vivo. The receptors involved in the angiogenic pathways, the specific motifs within the proteins responsible for the activities, the mechanism of secretion, and the cell signals responsible for secretion will investigated. These investigation will clarify how these components of the translation apparatus link protein synthesis to signal transduction pathways. The results of these studies can provide one kind of foundation for treating human diseases where cytokine activities and angiogenesis play an important role.
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