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Location: Jean Mayer Human Nutrition Research Center On Aging

Title: Modulation of phosphorylation of tocopherol and phosphatidylinositol by hTAP1/SEC14L2-mediated lipid exchange

item Zingg, Jean-marc
item Libinaki, Roksan
item Meydani, Mohsen
item Azzi, Angelo

Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/9/2014
Publication Date: 7/1/2014
Citation: Zingg, J., Libinaki, R., Meydani, M., Azzi, A. 2014. Modulation of phosphorylation of tocopherol and phosphatidylinositol by hTAP1/SEC14L2-mediated lipid exchange. PLoS One. 9:(7),e101550,1-10.

Interpretive Summary: An activated form of vitamin E (known as phosphorylated tocopherol) stimulates increased levels of a protein called VEGF (vascular endothelial growth factor). VEGF creates new blood vessels as in the formation of blood vessels in developing fetuses. Also, after birth, new blood vessels need to be created to replace existing ones such as after injury or in the muscles after exercise. However, too much expression of VEGF can contribute to disease development. For example, tumors require blood vessels to feed their growth, and VEGF works to form the blood vessels to the tumor to nourish its formation. We have discovered a specific protein that helps to diminish increased production of the VEGF protein. This protein is controlled by the activated form of vitamin E. This special protein should be further investigated given its ability to modify the expression of VEGF and given the impact it might have on the vascular (heart-blood vessels) system of the body both in health and in disease.

Technical Abstract: The vitamin E derivative, alpha-tocopheryl phosphate (aTP), is detectable in cultured cells, plasma and tissues in small amounts, suggesting the existence of enzyme(s) with a-tocopherol (aT) kinase activity. Here, we characterize the production of aTP from aT and [g-32P]-ATP in primary human coronary artery smooth muscle cells (HCA-SMC) using separation by thin layer chromatography (TLC) and subsequent analysis by Ultra Performance Liquid Chromatography (UPLC). In addition to aT, although to a lower amount, also gammaT is phosphorylated. In THP-1 monocytes, gammaTP inhibits cell proliferation and reduces CD36 scavenger receptor expression more potently than aTP. Both aTP and gammaTP activate the promoter of the human vascular endothelial growth factor (VEGF) gene with similar potency, whereas aT and gT had no significant effect. The recombinant human tocopherol associated protein 1 (hTAP1, hSEC14L2) binds both aT and aTP and stimulates phosphorylation of aT possibly by facilitating its transport and presentation to a putative aT kinase. Recombinant hTAP1 reduces the in vitro activity of the phosphatidylinositol-3-kinase gamma (PI3Kg) most likely by forming a stalled/inactive hTAP1/PI3Kg heterodimer. The addition aT, betaT, gammaT, deltaT or aTP differentially stimulates PI3Kgamma, possibly by facilitating egress of sequestered PI from hTAP1 to the enzyme. It is suggested that the continuous competitive exchange of different lipophilic ligands in the metabolic nanoreactor formed by hTAPs with cell enzymes and membranes may be a way to make these lipophiles more accessible as substrates for enzymes and as components of specific membrane domains.