PUBLICATION
Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis
- Authors
- Shi, Y., Liu, Z., Zhang, Q., Vallee, I., Mo, Z., Kishi, S., Yang, X.L.
- ID
- ZDB-PUB-201223-7
- Date
- 2020
- Source
- PLoS Biology 18: e3000991 (Journal)
- Registered Authors
- Kishi, Shuji
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inducing Agents
- Animals
- Animals, Genetically Modified
- Ataxia Telangiectasia/genetics
- Ataxia Telangiectasia Mutated Proteins/genetics
- Ataxia Telangiectasia Mutated Proteins/metabolism*
- Ataxia Telangiectasia Mutated Proteins/physiology
- Cell Line
- Female
- HEK293 Cells
- Humans
- Hypoxia/metabolism
- Hypoxia/physiopathology
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Mice
- Mice, Nude
- Neovascularization, Pathologic/genetics*
- Phosphorylation
- Serine-tRNA Ligase/metabolism*
- Serine-tRNA Ligase/physiology
- Transcription Factors/metabolism
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Xenograft Model Antitumor Assays/methods
- Zebrafish/metabolism
- Zebrafish Proteins/metabolism
- PubMed
- 33351793 Full text @ PLoS Biol.
Citation
Shi, Y., Liu, Z., Zhang, Q., Vallee, I., Mo, Z., Kishi, S., Yang, X.L. (2020) Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis. PLoS Biology. 18:e3000991.
Abstract
Hypoxia-induced angiogenesis maintains tissue oxygen supply and protects against ischemia but also enhances tumor progression and malignancy. This is mediated through activation of transcription factors like hypoxia-inducible factor 1 (HIF-1) and c-Myc, yet the impact of hypoxia on negative regulators of angiogenesis is unknown. During vascular development, seryl-tRNA synthetase (SerRS) regulates angiogenesis through a novel mechanism by counteracting c-Myc and transcriptionally repressing vascular endothelial growth factor A (VEGFA) expression. Here, we reveal that the transcriptional repressor role of SerRS is inactivated under hypoxia through phosphorylation by ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and RAD3-related (ATR) at Ser101 and Ser241 to attenuate its DNA binding capacity. In zebrafish, SerRSS101D/S241D, a phosphorylation-mimicry mutant, cannot suppress VEGFA expression to support normal vascular development. Moreover, expression of SerRSS101A/S241A, a phosphorylation-deficient and constitutively active mutant, prevents hypoxia-induced binding of c-Myc and HIF-1 to the VEGFA promoter, and activation of VEGFA expression. Consistently, SerRSS101A/S241A strongly inhibits normal and tumor-derived angiogenesis in mice. Therefore, we reveal a key step regulating hypoxic angiogenesis and highlight the importance of nuclear SerRS in post-developmental angiogenesis regulation in addition to vascular development. The role of nuclear SerRS in inhibiting both c-Myc and HIF-1 may provide therapeutic opportunities to correct dysregulation of angiogenesis in pathological settings.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping