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

Taro Matsumoto; 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

doi:10.1038/sj.emboj.7600709

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

Taro Matsumoto, 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

Jacksonville, FL

Research output: Contribution to journal › Article › peer-review

201 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2342-2353
Number of pages	12
Journal	EMBO Journal
Volume	24
Issue number	13
DOIs	https://doi.org/10.1038/sj.emboj.7600709
State	Published - Jul 6 2005

Keywords

Actin cytoskeleton
TSAd
Tumor angiogenesis
Tyrosine phosphorylation site
VEGFR-2

ASJC Scopus subject areas

Neuroscience(all)
Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.1038/sj.emboj.7600709

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Matsumoto, T., Bohman, S., Dixelius, J., Berge, T., Dimberg, A., Magnusson, P., Wang, L., Wikner, C., Qi, J. H., Wernstedt, C., Wu, J., Bruheim, S., Mugishima, H., Mukhopadhyay, D., Spurkland, A., & Claesson-Welsh, L. (2005). VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO Journal, 24(13), 2342-2353. https://doi.org/10.1038/sj.emboj.7600709

Matsumoto, T, Bohman, S, Dixelius, J, Berge, T, Dimberg, A, Magnusson, P, Wang, L, Wikner, C, Qi, JH, Wernstedt, C, Wu, J, Bruheim, S, Mugishima, H, Mukhopadhyay, D, Spurkland, A & Claesson-Welsh, L 2005, 'VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis', EMBO Journal, vol. 24, no. 13, pp. 2342-2353. https://doi.org/10.1038/sj.emboj.7600709

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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.",

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AU - Dimberg, Anna

AU - Magnusson, Peetra

AU - Wang, Ling

AU - Wikner, Charlotte

AU - Qi, Jian Hua

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AU - Wu, Jiong

AU - Bruheim, Skjalg

AU - Mugishima, Hideo

AU - Mukhopadhyay, Debrabata

AU - Spurkland, Anne

AU - Claesson-Welsh, Lena

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

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