Jiang, B.H. , Zheng, J.Z. , Aoki, M. & Vogt, P.K. Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc. Natl. Acad. Sci. USA 97, 1749-1753

The Scripps Research Institute, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2000; 97(4):1749-53. DOI: 10.1073/pnas.040560897
Source: PubMed


Phosphatidylinositol 3-kinase (PI 3-kinase) is a signaling molecule that controls numerous cellular properties and activities. The oncogene v-p3k is a homolog of the gene coding for the catalytic subunit of PI 3-kinase, p110alpha. P3k induces transformation of cells in culture, formation of hemangiosarcomas in young chickens, and myogenic differentiation in myoblasts. Here, we describe a role of PI 3-kinase in angiogenesis. Overexpression of the v-P3k protein or of cellular PI 3-kinase equipped with a myristylation signal, Myr-P3k, can induce angiogenesis in the chorioallantoic membrane (CAM) of the chicken embryo. This process is characterized by extensive sprouting of new blood vessels and enlargement of preexisting vessels. Overexpression of the myristylated form of the PI 3-kinase target Akt, Myr-Akt, also induces angiogenesis. Overexpression of the tumor suppressor PTEN or of dominant-negative constructs of PI 3-kinase inhibits angiogenesis in the yolk sac of chicken embryos, suggesting that PI 3-kinase and Akt signaling is required for normal embryonal angiogenesis. The levels of mRNA for vascular endothelial growth factor (VEGF) are elevated in cells expressing activated PI 3-kinase or Myr-Akt. VEGF mRNA levels are also increased by insulin treatment through the PI 3-kinase-dependent pathway. VEGF mRNA levels are decreased in cells treated with the PI 3-kinase inhibitor LY294002 and restored by overexpression of v-P3k or Myr-Akt. Overexpression of VEGF by the RCAS vector induces angiogenesis in chicken embryos. These results suggest that PI 3-kinase plays an important role in angiogenesis and regulates VEGF expression.

  • Source
    • "tumor growth, and angiogenesis [18] [19]. Downstream substrates of AKT include the FoxO transcription factors, GSK3, BAD, p27, Skp2, and p21, which have important roles in the regulation of the cell cycle, cell growth, migration, and apoptosis [20] [21] [22]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Thrombin and its membrane receptor, protease-activated receptor 1 (PAR1), have been reported to promote the development of lung cancer in vitro and in vivo. However, the intracellular molecular mechanism or signaling pathway that mediates the cytological effects after the thrombin-receptor interaction is poorly understood. Our previous study observed that the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was downregulated in thrombin-stimulated lung cancer. In this study, the role of PTEN in thrombin-mediated cell function and the corresponding cell signaling pathway were studied in lung cancer cell Glc-82. The results indicated that thrombin downregulates the PTEN expression level and that PTEN plays an important role in thrombin-mediated Glc-82 functions, including cell cycle progression, cell apoptosis, and cell migration. The PI3K/AKT signaling pathway and its related proteins, including p27 and S phase kinase associated protein 2 (Skp2), are involved in the effects induced by PTEN downregulation. PAR1 plays a role in thrombin-mediated reduction of PTEN expression. This study suggested that the PTEN/PI3K/AKT signaling pathway plays an important role in thrombin/PAR1-mediated lung cancer cell growth and migration.
    Full-text · Article · Apr 2015
  • Source
    • "of the PI3K signaling pathway reduces VEGF expression and interferes with vasculogenesis and angiogenesis [30], resulting in severe defects in vascular sprouting and remodeling [31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many important cellular functions. The functional impact of deregulating the PIK3CA gene, encoding the p110α catalytic subunit of PI3K, is validated by frequent gain of function mutations in a range of human cancers. We generated a mouse model with an inducible constitutively active form of PI3K. In this model Cre recombinase activates expression of a myristoylated form of p110α (myr-p110α). The myristoylated version of p110α brings the protein to the cytoplasmic side of the cell membrane, which mimics the normal activation mechanism for the p110α catalytic subunit and activates the PI3K enzyme. Constitutively activated PI3K signaling induced by myr-p110α in all cells of the developing mouse caused lethality during embryonic development. Transgenic Cre;myr-p110α heterozygous embryos displayed morphological malformation and poor vascular development with extremely dilated blood vessels and hemorrhage in the embryo and the extraembryonic yolk sac. Previous studies demonstrated that loss of p110α during embryonic development causes angiogenic disruption and here we show that constitutive activation of p110α by gain of function mutation during development also disrupts vasculogenesis/angiogenesis in what appears to be a similar manner. These finding demonstrate the importance of tight regulation of PI3K signaling during embryonic vasculogenesis/angiogenesis.
    Full-text · Article · Jan 2015
  • Source
    • "The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling pathway is a candidate therapeutic target for angiogenesis [16], [17]. The PI3K family are closely related lipid kinases regulating cell metabolism, growth, survival, migration and angiogenesis [18], [19]. PI3K family members are sub-classified based on structural features and substrate specificity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ocular neovascularization is a common pathology associated with human eye diseases e.g. age-related macular degeneration and proliferative diabetic retinopathy. Blindness represents one of the most feared disabilities and remains a major burden to health-care systems. Current approaches to treat ocular neovascularisation include laser photocoagulation, photodynamic therapy and anti-VEGF therapies: Ranibizumab (Lucentis) and Aflibercept (Eylea). However, high clinical costs, frequent intraocular injections, and increased risk of infections are challenges related with these standards of care. Thus, there is a clinical need to develop more effective drugs that overcome these challenges. Here, we focus on an alternative approach by quantifying the in vivo anti-angiogenic efficacy of combinations of phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. The PI3K/AKT/mTOR pathway is a complex signalling pathway involved in crucial cellular functions such as cell proliferation, migration and angiogenesis. RT-PCR confirms the expression of PI3K target genes (pik3ca, pik3r1, mtor and akt1) in zebrafish trunks from 6 hours post fertilisation (hpf) and in eyes from 2 days post fertilisation (dpf). Using both the zebrafish intersegmental vessel and hyaloid vessel assays to measure the in vivo anti-angiogenic efficacy of PI3K/Akt/mTOR pathway inhibitors, we identified 5 µM combinations of i) NVP-BEZ235 (dual PI3K-mTOR inhibitor) + PI-103 (dual PI3K-mTOR inhibitor); or ii) LY-294002 (pan-PI3K inhibitor) + NVP-BEZ235; or iii) NVP-BEZ235 + rapamycin (mTOR inhibitor); or iv) LY-294002 + rapamycin as the most anti-angiogenic. Treatment of developing larvae from 2-5 dpf with 5 µM NVP-BEZ235 plus PI-103 resulted in an essentially intact ocular morphology and visual behaviour, whereas other combinations severely disrupted the developing retinal morphology and visual function. In human ARPE19 retinal pigment epithelium cells, however, no significant difference in cell number was observed following treatment with the inhibitor combinations. Collectively, these results highlight the potential of combinations of PI3K/AKT/mTOR pathway inhibitors to safely and effectively treat ocular neovascularization.
    Full-text · Article · Aug 2014 · PLoS ONE
Show more