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

EMBO J. 2005 Jul 6;24(13):2342-53. doi: 10.1038/sj.emboj.7600709. Epub 2005 Jun 16.


Vascular endothelial growth factor receptor-2 (VEGFR-2) activation by VEGF-A is essential in vasculogenesis and angiogenesis. We have generated a pan-phosphorylation site map of VEGFR-2 and identified one major tyrosine phosphorylation site in the kinase insert (Y951), in addition to two major sites in the C-terminal tail (Y1175 and Y1214). In developing vessels, phosphorylation of Y1175 and Y1214 was detected in all VEGFR-2-expressing endothelial cells, whereas phosphorylation of Y951 was identified in a subset of vessels. Phosphorylated Y951 bound the T-cell-specific adapter (TSAd), which was expressed in tumor vessels. Mutation of Y951 to F and introduction of phosphorylated Y951 peptide or TSAd siRNA into endothelial cells blocked VEGF-A-induced actin stress fibers and migration, but not mitogenesis. Tumor vascularization and growth was reduced in TSAd-deficient mice, indicating a critical role of Y951-TSAd signaling in pathological angiogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Fibrosarcoma / blood supply
  • Humans
  • Kidney Neoplasms / blood supply
  • Mice
  • Molecular Sequence Data
  • Neovascularization, Pathologic / metabolism*
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Signal Transduction*
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Tyrosine / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Actins
  • Adaptor Proteins, Signal Transducing
  • RNA, Small Interfering
  • Tyrosine
  • Vascular Endothelial Growth Factor Receptor-2