Figure 1

The direct pathway of action of RNASE5. The proposed mechanism of action as determined from a review of the literature. Hypoxic stress triggers transcription of RNASE5[37]. RNASE5 triggers the expression of two cell-density dependent receptors. At higher cell densities, RNASE5 binds with the endothelial cell surface via a 42-kDa α-actin receptor which stimulates basement membrane degradation[18]. This complex triggers plasminogen activation which in turn stimulates endothelial cell migration and angiogenesis[18, 45]. Once the cell density decreases, the 170 kDa RNASE5 receptor is synthesized[19]. Binding interactions with this 170 kDa cell surface receptor trigger endocytosis of RNASE5[19]. Once internalised, RNASE5 triggers a series of cell signalling pathways including second messenger responses, MAPK activation and phosphorylation of Erk1/2 which stimulate cell proliferation, migration and growth[46–48]. From the cytoplasm, RNASE5 is translocated to the nucleus where it enhances rRNA transcription[20]. RNASE5 cleaves rRNA and tRNA and in turn recombinant angiogenin has been shown to act as a cytotoxic tRNase that abolishes protein synthesis[49–51]. We also revealed a significant number of activators and inhibitors of this pathway e.g. NO, however, only proteins were considered[52]. The path of the RNASE5 protein is highlighted in red boxes, with blue boxes representing the subsequent processes. The genes involved in this process are dictated alongside each process with activators and inhibitors noted outside each process in red (inhibitors) and black (up-regulators and other known binding proteins).