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VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis

Taro Matsumoto1, Svante Bohman, Johan Dixelius

  • 1Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.

The EMBO Journal
|June 18, 2005
PubMed

Insights

Vascular endothelial growth factor receptor-2 (VEGFR-2) Y951 phosphorylation binds T-cell-specific adapter (TSAd), crucial for tumor angiogenesis and growth. Inhibiting this pathway reduces tumor vascularization and growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Vascular endothelial growth factor receptor-2 (VEGFR-2) activation by VEGF-A is critical for blood vessel formation.
  • Understanding VEGFR-2 phosphorylation sites is key to elucidating its role in angiogenesis.

Purpose of the Study:

  • To map pan-phosphorylation sites of VEGFR-2.
  • To investigate the functional role of a specific phosphorylation site, Y951, and its interaction with T-cell-specific adapter (TSAd) in angiogenesis.

Main Methods:

  • Generated a pan-phosphorylation site map of VEGFR-2.
  • Utilized cell-based assays with mutated VEGFR-2 (Y951F), phosphorylated Y951 peptide, and TSAd siRNA.
  • Assessed tumor vascularization and growth in TSAd-deficient mice.

Main Results:

  • Identified major VEGFR-2 phosphorylation sites: Y951 (kinase insert) and Y1175, Y1214 (C-terminal tail).
  • Phosphorylated Y951 specifically binds TSAd, which is present in tumor vessels.
  • Blocking Y951-TSAd signaling inhibited VEGF-A-induced endothelial cell migration and actin stress fiber formation, but not proliferation.
  • TSAd deficiency reduced tumor vascularization and growth in mice.

Conclusions:

  • VEGFR-2 Y951 phosphorylation and its interaction with TSAd play a critical role in pathological angiogenesis.
  • The Y951-TSAd signaling pathway is a potential therapeutic target for inhibiting tumor growth by disrupting tumor vascularization.

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