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Phosphoproteomic analysis implicates the mTORC2-FoxO1 axis in VEGF signaling and feedback activation of receptor

Guanglei Zhuang1, Kebing Yu, Zhaoshi Jiang

  • 1Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Science Signaling
|April 18, 2013
PubMed

Insights

Vascular endothelial growth factor (VEGF) signaling drives angiogenesis. The PI3K-mTORC2-FoxO1 axis regulates VEGF responses in endothelial cells, impacting tumor growth and neovascular disorders.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Angiogenesis research

Background:

  • Vascular endothelial growth factor (VEGF) signaling is crucial for normal development and pathological angiogenesis.
  • VEGF receptor tyrosine kinases mediate angiogenesis by phosphorylating downstream targets in endothelial cells.
  • Understanding VEGF-regulated phosphoproteome dynamics is vital for therapeutic targeting.

Purpose of the Study:

  • To define the VEGF-regulated phosphoproteome and its temporal dynamics in human umbilical vein endothelial cells.
  • To investigate the function of phosphorylated proteins in VEGF responses using siRNA screens.
  • To elucidate the role of the PI3K-mTORC2-FoxO1 axis in VEGF signaling.

Main Methods:

  • Large-scale proteomic analysis of the phosphoproteome.
  • siRNA screening to assess protein function.
  • Investigation of signaling pathways in human umbilical vein endothelial cells.

Main Results:

  • The PI3K-mTORC2 axis centralizes VEGF-regulated phosphorylation and endothelial cell viability.
  • This axis suppresses FoxO1 activity, limiting apoptosis and feedback receptor tyrosine kinase activation.
  • The mTORC2-FoxO1 axis influences therapeutic responses to PI3K and mTOR inhibitors.

Conclusions:

  • The study provides a dynamic, global view of VEGF-regulated phosphorylation.
  • The mTORC2-FoxO1 axis is implicated in VEGF receptor signaling and receptor tyrosine kinase reprogramming.
  • This axis represents a potential therapeutic target for angiogenesis-related disorders.

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