Journal ArticleDOI
The second immunoglobulin-like domain of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding and may initiate a signal transduction cascade.
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TLDR
It is demonstrated that a single Ig‐like domain is the major determinant for VEGF‐PlGF interaction and that binding to this domain may initiate a signal transduction cascade.Abstract:
Vascular endothelial growth factor (VEGF) is an angiogenic inducer that mediates its effects through two high affinity receptor tyrosine kinases, Flt-1 and KDR. Flt-1 is required for endothelial cell morphogenesis whereas KDR is involved primarily in mitogenesis. Flt-1 has an alternative ligand, placenta growth factor (PlGF). Both Flt-1 and KDR have seven immunoglobulin (Ig)-like domains in the extracellular domain. The significance and function of these domains for ligand binding and receptor activation are unknown. Here we show that deletion of the second domain of Flt-1 completely abolishes the binding of VEGF. Introduction of the second domain of KDR into an Flt-1 mutant lacking the homologous domain restored VEGF binding. However, the ligand specificity was characteristic of the KDR receptor. We then created chimeric receptors where the first three or just the second Ig-like domains of Flt-1 replaced the corresponding domains in Flt-4, a receptor that does not bind VEGF, and analyzed their ability to bind VEGF. Both swaps conferred upon Flt-4 the ability to bind VEGF with an affinity nearly identical to that of wild-type Flt-1. Furthermore, transfected cells expressing these chimeric Flt-4 receptors exhibited increased DNA synthesis in response to VEGF or PlGF. These results demonstrate that a single Ig-like domain is the major determinant for VEGF-PlGF interaction and that binding to this domain may initiate a signal transduction cascade.read more
Citations
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Journal ArticleDOI
The biology of VEGF and its receptors.
TL;DR: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions and is implicated in pathologicalAngiogenesis associated with tumors, intraocular neovascular disorders and other conditions.
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The biology of vascular endothelial growth factor
TL;DR: The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult.
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Vascular endothelial growth factor (VEGF) and its receptors
TL;DR: Recent developments that have widened considerably the understanding of the mechanisms that control V EGF production and VEGF signal transduction are focused on and recent studies that have shed light on the mechanisms by which VEGf regulates angiogenesis are reviewed.
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Vascular endothelial growth factor: basic science and clinical progress.
TL;DR: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models and is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.
Journal ArticleDOI
Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer
TL;DR: The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blockingAngiogenesis is an effective strategy to treat human cancer.
References
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Angiogenesis in cancer, vascular, rheumatoid and other disease
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Journal ArticleDOI
Signal transduction by receptors with tyrosine kinase activity
Axel Ullrich,Joseph Schlessinger +1 more
TL;DR: Cet article synthese montre comment des recepteurs membranaires a activite tyrosine kinase peuvent etre impliques dans la transduction and notamment jouent le role de signal de the transduction.
Journal ArticleDOI
Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele
Peter Carmeliet,Valérie Ferreira,Georg Breier,Saskia Pollefeyt,Lena Kieckens,Marina Gertsenstein,Michaela Fahrig,Ann Vandenhoeck,Kendraprasad Harpal,Carmen Eberhardt,Cathérine Declercq,Judy Pawling,Lieve Moons,Desire Collen,Werner Risau,Andras Nagy,Andras Nagy +16 more
TL;DR: It is reported that formation of blood vessels was abnormal, but not abolished, in heterozygous VEGF-deficient (VEGF+/-) embryos, generated by aggregation of embryonic stem (ES) cells with tetraploid embryos (T-ES)16,17, and even more impaired in homozygous D1-VEGF- deficient (VDGF-/-) T-ES embryos, resulting in death at mid-gestation.
Journal ArticleDOI
Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.
Fouad Shalaby,Janet Rossant,Janet Rossant,Terry P. Yamaguchi,Terry P. Yamaguchi,Marina Gertsenstein,Xiang-Fu Wu,Xiang-Fu Wu,Martin L. Breitman,Martin L. Breitman,Andre C. Schuh +10 more
TL;DR: The generation of mice deficient in Flk-1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells is reported, indicating that FlK-1 is essential for yolk-sac blood-island formation and vasculogenesis in the mouse embryo.