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.
Taro Matsumoto  1 ,  Svante Bohman ,  Johan Dixelius ,  Tone Berge ,  Anna Dimberg ,  Peetra Magnusson ,  Ling Wang ,  Charlotte Wikner ,  Jian Hua Qi ,  Christer Wernstedt ,  Jiong Wu ,  Skjalg Bruheim ,  Hideo Mugishima ,  Debrabata Mukhopadhyay ,  Anne Spurkland ,  Lena Claesson-Welsh
Affiliations
  • 1. Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
PMID: 15962004 DOI: 10.1038/sj.emboj.7600709
Abstract

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.