Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis. Proc Natl Acad Sci U S A

Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2007; 104(9):3243-8. DOI: 10.1073/pnas.0611510104
Source: PubMed

ABSTRACT Development of the vascular system depends on the highly coordinated actions of a variety of angiogenic regulators. Several of these regulators are members of the tyrosine kinase superfamily, including VEGF receptors and angiopoietin receptors, Tie1 and Tie2. Tyrosine kinase signaling is counter-regulated by the activity of tyrosine phosphatases, including vascular endothelial protein tyrosine phosphatase (VE-PTP), which has previously been shown to modulate Tie2 activity. We generated mice in which VE-PTP is replaced with a reporter gene. We confirm that VE-PTP is expressed in endothelium and also show that VE-PTP is highly expressed in the developing outflow tract of the heart and later is expressed in developing heart valves. Vasculogenesis occurs normally in mice lacking VE-PTP; however, angiogenesis is abnormal. Angiogenic defects in VE-PTP-null mice were most pronounced in the yolk sac and include a complete failure to elaborate the primitive vascular scaffold into higher-order branched arteries, veins, and capillaries. VE-PTP continues to be expressed into adulthood in the vasculature and heart valves, suggesting later roles in vascular development or homeostasis. VE-PTP is also expressed in the vasculature of growing tumors, suggesting that VE-PTP may be a new potential target for angiogenic therapies.

  • Source
    • "There are several ubiquitous protein phosphatases but currently only one vascular specific protein phosphatase is known; vascular endothelial-protein phosphatase (VE-PTP). This protein is a transmembrane tyrosine phosphatase essential for normal angiogenesis and embryogenesis (Dominguez et al., 2007). Hence, it is of great interest to identify and Fig. 8 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenesis is implicated in many pathological conditions. The role of the proteins involved remains largely unknown, and few vascular-specific drug targets have been discovered. Previously, in a screen for angiogenesis regulators, we identified Paladin (mouse: X99384, human: KIAA1274), a protein containing predicted S/T/Y phosphatase domains. We present a mouse knockout allele for Paladin with a β-galactosidase reporter, which in combination with Paladin antibodies demonstrate that Paladin is expressed in the vasculature. During mouse embryogenesis, Paladin is primarily expressed in capillary and venous endothelial cells. In adult mice Paladin is predominantly expressed in arterial pericytes and vascular smooth muscle cells. Paladin also displays vascular-restricted expression in human brain, astrocytomas, and glioblastomas. Paladin, a novel putative phosphatase, displays a dynamic expression pattern in the vasculature. During embryonic stages it is broadly expressed in endothelial cells, while in the adult it is selectively expressed in arterial smooth muscle cells.
    Developmental Dynamics 04/2012; 241(4):770-86. DOI:10.1002/dvdy.23753 · 2.67 Impact Factor
  • Source
    • "Many genes misregulated in diseases such as cancer exhibit embryonic lethal phenotypes in knockout mouse models. For example, the disruption of genes involved in angiogenesis such as vascular endothelial growth factor or vascular endothelial receptor tyrosine phosphatase results in vascular defects, leading to embryonic lethality (Carmeliet et al., 1996; Dominguez et al., 2007) and precluding study of the roles of these proteins in tumor angiogenesis. The DHFR-derived DD system may be a suitable alternative for in vivo regulation of proteins that are required during embryonic development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ability to make specific perturbations to biological molecules in a cell or organism is a central experimental strategy in modern research biology. We have developed a general technique in which the stability of a specific protein is regulated by a cell-permeable small molecule. Mutants of the Escherichia coli dihydrofolate reductase (ecDHFR) were engineered to be degraded, and, when this destabilizing domain is fused to a protein of interest, its instability is conferred to the fused protein resulting in rapid degradation of the entire fusion protein. A small-molecule ligand trimethoprim (TMP) stabilizes the destabilizing domain in a rapid, reversible, and dose-dependent manner, and protein levels in the absence of TMP are barely detectable. The ability of TMP to cross the blood-brain barrier enables the tunable regulation of proteins expressed in the mammalian central nervous system.
    Chemistry & biology 09/2010; 17(9):981-8. DOI:10.1016/j.chembiol.2010.07.009 · 6.59 Impact Factor
  • Source
    • "This is in contrast to the large diameter EC-lined cavity that formed when the spheroids were cultured in VEGF-supplemented medium. Based on previous studies in which elevated VEGF levels were shown to promote the formation of large diameter vessels and vascular sinuses via the fusion of small diameter vessels (Drake and Little, 1995; Drake and Fleming, 2000; Argraves et al., 2002; Dor et al., 2002; Dominguez et al., 2007 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Embryonic mouse allantoic tissue (E8.5) was cultured in hanging drops to generate a three-dimensional vascular micro-tissue. The resulting tissue spheroids had an inner network of small diameter vessels expressing platelet endothelial cell adhesion molecule-1 (PECAM-1) and an outer layer of cells expressing SMαA, SM22-α, and SM-MHC. In a subsequent phase of culture, the fusion-promoting activity of vascular endothelial growth factor (VEGF) was used to transform the inner network of small diameter endothelial tubes into a contiguous layer of cells expressing PECAM-1, CD34, and VE-cadherin that circumscribed a central lumen-like cavity. The blood vessel-like character of the VEGF-treated spheroids was further demonstrated by their physiologically relevant vasodilatory and contractile responses, including contraction induced by KCl and relaxation stimulated by high-density lipoproteins and acetylcholine-induced nitric oxide production. Developmental Dynamics 237:2918–2925, 2008.
    Developmental Dynamics 10/2008; 237(12):spc1. DOI:10.1002/dvdy.21825 · 2.67 Impact Factor
Show more


Available from