期刊
EMBO JOURNAL
卷 24, 期 13, 页码 2342-2353出版社
WILEY
DOI: 10.1038/sj.emboj.7600709
关键词
actin cytoskeleton; TSAd; tumor angiogenesis; tyrosine phosphorylation site; VEGFR-2
资金
- NHLBI NIH HHS [R01 HL070567, HL70567, HL072178, R01 HL072178] Funding Source: Medline
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.
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