Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway

Castranova, D., Davis, A.E., Lo, B.D., Miller, M.F., Paukstelis, P.J., Swift, M.R., Pham, V.N., Torres-Vázquez, J., Bell, K., Shaw, K.M., Kamei, M., Weinstein, B.M.
Arteriosclerosis, Thrombosis, and Vascular Biology   36(4): 655-62 (Journal)
Registered Authors
Castranova, Dan, Davis, Andrew, Kamei, Makoto, Lo, Brigid, Miller, Mayumi, Pham, Van, Swift, Matthew Russell, Weinstein, Brant M.
endoplasmic reticulum, protein kinases, unfolded protein response, vascular endothelial growth factor A, zebrafish
MeSH Terms
  • Activating Transcription Factor 4/genetics
  • Activating Transcription Factor 4/metabolism
  • Activating Transcription Factor 6/genetics
  • Activating Transcription Factor 6/metabolism
  • Animals
  • Animals, Genetically Modified
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism
  • Endoplasmic Reticulum/metabolism
  • Endoplasmic Reticulum Stress
  • Gene Expression Regulation, Developmental
  • Genotype
  • Isoleucine-tRNA Ligase/deficiency*
  • Isoleucine-tRNA Ligase/genetics
  • Mutation
  • Neovascularization, Physiologic*
  • Phenotype
  • Regulatory Factor X Transcription Factors
  • Signal Transduction
  • Threonine-tRNA Ligase/deficiency*
  • Threonine-tRNA Ligase/genetics
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Unfolded Protein Response*
  • Vascular Endothelial Growth Factor A/genetics
  • Vascular Endothelial Growth Factor A/metabolism
  • X-Box Binding Protein 1
  • Zebrafish
  • Zebrafish Proteins/deficiency*
  • Zebrafish Proteins/genetics
26821951 Full text @ Arterio., Thromb., and Vas. Bio.
Understanding the mechanisms regulating normal and pathological angiogenesis is of great scientific and clinical interest. In this report, we show that mutations in 2 different aminoacyl-transfer RNA synthetases, threonyl tRNA synthetase (tars(y58)) or isoleucyl tRNA synthetase (iars(y68)), lead to similar increased branching angiogenesis in developing zebrafish.
The unfolded protein response pathway is activated by aminoacyl-transfer RNA synthetase deficiencies, and we show that unfolded protein response genes atf4, atf6, and xbp1, as well as the key proangiogenic ligand vascular endothelial growth factor (vegfaa), are all upregulated in tars(y58) and iars(y68) mutants. Finally, we show that the protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 arm of the unfolded protein response pathway is necessary for both the elevated vegfaa levels and increased angiogenesis observed in tars(y58) mutants.
Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway-dependent upregulation of vegfaa.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes