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Vascular Endothelial Growth Factor (VEGF)-A165b Is a Weak In vitro Agonist for VEGF Receptor-2 Due to Lack of Coreceptor Binding and Deficient Regulation of Kinase Activity
Abstract
Vascular endothelial growth factor (VEGF)-A165b is a COOH-terminal splice variant of VEGF-A that has been implicated in negative regulation of angiogenesis. We compared the properties of VEGF-A165b with those of VEGF-A121, VEGF-A145, and VEGF-A165. Induction of tyrosine phosphorylation sites in VEGFR-2 differed between the VEGF ligands as determined by tryptic phosphopeptide mapping and by use of phosphosite-specific antibodies. VEGF-A165b was considerably poorer in inducing phosphorylation of the positive regulatory site Y1052 in VEGFR-2. Whereas this did not affect activation of VEGFR-2 in vitro, we show that VEGF-A165b failed to induce vasculogenesis and sprouting angiogenesis in differentiating embryonic stem cells and vascularization of s.c. Matrigel plugs. In addition, the ability of the different VEGF ligands to induce angiogenesis correlated with their abilities to bind the VEGF coreceptor neuropilin 1 (NRP1). Our data indicate that loss of VEGFR-2/NRP1 complex formation and Y1052 phosphorylation contribute to the lack of angiogenic properties of VEGF-A165b. [Cancer Res 2008;68(12):4683–92]
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“By ineffectively occupying a binding site on the receptor, the VEGFXXXb isoforms inhibit the function of the VEGFXXX variants [36, 200].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [36]
In the citing paper
“The VEGF “B” splice variants are generated by use of an alternate 3’ acceptor site for exon 8, lengthening the intrinsically disordered C-terminal tail by an additional 6 amino acids (e.g., VEGF165 versus VEGF165b) [36, 200].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [36]
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Metadata
- Authors
- Kawamura, H., Li, X., Harper, S. J., Bates, D. O., & Claesson-Welsh, L.
- Affiliations
- Uppsala University (SE)
- University of Bristol (GB)
- 1Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; and
- Venue
- Cancer Research
- Published
- 2008-06-15
- Volume
- 68
- Issue
- 12
- Pages
- 4683-4692
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2067020920
- Cited by
- 156
- References
- 31
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 4 · 2019: 10 · 2018: 13 · 2017: 11 · 2016: 10 · 2015: 11 · 2014: 14 · 2013: 9 · 2012: 11
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- VEGF-A165b, VEGF splice variants, VEGF receptor 2, neuropilin-1, tyrosine phosphorylation, kinase regulation, angiogenesis, vasculogenesis, sprouting angiogenesis, embryonic stem cells
- MeSH terms
- Animals, Aorta, Binding, Competitive, Cell Differentiation, Cells, Cultured, Chemotaxis, Collagen, Drug Combinations, Embryo, Mammalian, Endothelium, Vascular, Female, Gene Expression Regulation, Heparitin Sulfate, Heparan Sulfate, Humans, Laminin, Mice, Nude, Phosphorylation, Protein Binding, Proteoglycans, Swine, Tyrosine, Immunoblotting, Signal Transduction, Neovascularization, Physiologic, Neuropilin-1, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Immunoprecipitation, Mice
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