Abstract
In several studies, vitamin E has been observed to influence angiogenesis and vasculogenesis. We recently showed that the phosphorylated form of alpha-tocopherol (alpha T), alpha-tocopheryl phosphate (alpha TP), increases the expression of the vascular endothelial growth factor (VEGF). Thus, alpha TP may act as an active lipid mediator increasing VEGF expression, angiogenesis, and vasculogenesis. Here, we investigated the molecular signaling mechanisms by which alpha TP induces VEGF expression using cultured HEK293 cells as model system. alpha T and more so alpha TP increased VEGF-promoter activity in a phosphatidylinositol-3-kinase gamma (PI3K gamma)-dependent manner. In contrast, after overexpression of PI3K gamma and/or protein kinase B (PKB), VEGF promoter activity was inhibited by alpha T and more so by alpha TP. Inhibition by alpha T and alpha TP was dependent on the lipid kinase activity of PI3K gamma, whereas an induction was seen with the protein kinase activity, consistent with a model in which PKB inhibition by alpha T or alpha TP occurs only when activated at the plasma membrane and possibly involves a phosphatase such as PHLPP1. PI3K gamma-induced VEGF expression was reduced when the human tocopherol-associated protein 1 (hTAP1/SEC14L2) was overexpressed suggesting formation of an inactive PI3K gamma/hTAP1 heterodimer, that could be reactivated by alpha T and more so by alpha TP. We suggest a novel signaling mechanism by which alpha TP stimulates PI3K gamma activity by stimulating hTAP-mediated phosphatidylinositol exchange and presentation to the enzyme and/or dissociation of an inactive heterodimer. At cellular level, hTAP may act as sensor for intracellular lipid information (location, type, and amount of lipid) and translate it into responses of PI3K-mediated signaling and gene expression. (C) 2014 Wiley Periodicals, Inc.
