MECHANISM OF PI3 KINASE INDUCED ANGIOGENESIS

West Virginia University, Morgantown WV

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Abstract

DESCRIPTION (provided by applicant): Phosphatidylinositol 3-kinase (PI 3- kinase) is activated upon activation of protein tyrosine kinase receptors by growth factors. PI 3-kinase and its target Akt have been shown to promote cell growth and inhibit apoptosis. Angiogenesis is required for tumorigenesis and the inhibition of angiogenesis represents one of the most promising approaches for cancer therapeutic treatment. The objectives of this study are to understand the signal transduction pathways initiated from PI 3-kinase during angiogenesis, and to generate information on the molecular mechanism of angiogenesis. The oncogenic form of PI 3-kinase, v-p3k, can directly induce cellular transformation and tumors in chicken. Activation of PI 3-kinase signaling is detected in many human cancers. Our recent studies demonstrated that expressions of active forms of PI 3-kinase and Akt alone strongly induce angiogenesis and hemangiosarcarcomas. Inhibition of PI 3-kinase activity using PI 3-kinase dominant negative construct or the tumor suppressor PTEN, inhibit embryonal angiogenesis. We have recently found that PI 3-kinase activates expression of VEGF. VEGF plays an important role in normal and pathological angiogenesis. We have also performed representational differential analysis, and identified the transferrin receptor (TfR) that is up-regulated by Akt. In this study, we will identify signaling molecules that are induced by PI 3-kinase and Akt during angiogenesis, and provide new insights into the mechanisms of angiogenesis in general. The specific aims will determine: 1) the role of VEGF and TfR in PI 3-kinase and Akt-induced angiogenesis; 2) the role of known targets of Akt in PI 3-kinase-induced angiogenesis, and whether PI 3-kinase and Akt affect cell cycle progression; 3) whether Akt mediates expression of other angiogenic factors; and 4) whether Akt affects actin filament via known actin filament-associated modulating proteins, such as AFAP-110.