title: VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis.
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.
authors.affiliation: Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Taro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Svante
authors.initials: S
authors.lastname: Bohman
authors.forename: Johan
authors.initials: J
authors.lastname: Dixelius
authors.forename: Tone
authors.initials: T
authors.lastname: Berge
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
authors.forename: Peetra
authors.initials: P
authors.lastname: Magnusson
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wikner
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Qi
authors.forename: Christer
authors.initials: C
authors.lastname: Wernstedt
authors.forename: Jiong
authors.initials: J
authors.lastname: Wu
authors.forename: Skjalg
authors.initials: S
authors.lastname: Bruheim
authors.forename: Hideo
authors.initials: H
authors.lastname: Mugishima
authors.forename: Debrabata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Anne
authors.initials: A
authors.lastname: Spurkland
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
mesh_terms: 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*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D034741:RNA, Small Interfering; D014443:Tyrosine; D040301:Vascular Endothelial Growth Factor Receptor-2