ZFIN ID: ZDB-PUB-201223-7
Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis
Shi, Y., Liu, Z., Zhang, Q., Vallee, I., Mo, Z., Kishi, S., Yang, X.L.
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.
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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.
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