VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis.
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.
Matsumoto
Taro
T
Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Bohman
Svante
S
Dixelius
Johan
J
Berge
Tone
T
Dimberg
Anna
A
Magnusson
Peetra
P
Wang
Ling
L
Wikner
Charlotte
C
Qi
Jian Hua
JH
Wernstedt
Christer
C
Wu
Jiong
J
Bruheim
Skjalg
S
Mugishima
Hideo
H
Mukhopadhyay
Debrabata
D
Spurkland
Anne
A
Claesson-Welsh
Lena
L
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005354:Fibrosarcoma / Q000098:blood supply; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply; D051379:Mice; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D034741:RNA, Small Interfering; D014443:Tyrosine; D040301:Vascular Endothelial Growth Factor Receptor-2