View the Current Issue

Article

  • The EMBO Journal (2005) 24, 2342 - 2353
  • doi:10.1038/sj.emboj.7600709

Published online: 16 June 2005

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

Taro Matsumoto1,2, Svante Bohman1, Johan Dixelius1, Tone Berge3, Anna Dimberg1, Peetra Magnusson1, Ling Wang4, Charlotte Wikner1, Jian Hua Qi5, Christer Wernstedt6, Jiong Wu7, Skjalg Bruheim8, Hideo Mugishima2, Debrabata Mukhopadhyay4, Anne Spurkland3 and Lena Claesson-Welsh1

  1. Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
  2. Division of Cell Regeneration and Transplantation, Advanced Medical Research Center, Nihon University School of Medicine, Ohyaguchikamimachi, Itabashi-ku, Tokyo, Japan
  3. Department of Anatomy, Institute of Basal Medical Sciences, University of Oslo, Blindern, Oslo, Norway
  4. Mayo Clinic Foundation, Gugg, Rochester, MN, USA
  5. Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
  6. Ludwig Institute for Cancer Research, Uppsala Branch, Biomedical Center, Uppsala, Sweden
  7. Cell Signaling Technology, Cummings Center, Beverly, MA, USA
  8. Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway

Correspondence to:

Lena Claesson-Welsh, Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Dag Hammarskjöldsv. 20, 75185 Uppsala, Sweden. Tel.: +46 18 471 43 63; Fax: +46 18 55 89 31; E-mail: lena.claesson-welsh@genpat.uu.se

Received 3 November 2004; Accepted 18 May 2005

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.

  • Keywords:

    • actin cytoskeleton,
    • TSAd,
    • tumor angiogenesis,
    • tyrosine phosphorylation site,
    • VEGFR-2