Alfa Tokoferoli ja PI voivat vaihtua fosfaatissa

https://globalmedicaldiscovery.com/key-scientific-articles/modulation-phosphorylation-tocopherol-phosphatidylinositol-htap1sec14l2-mediated-lipid-exchange/

Phosphorylated, but not un-phosphorylated tocopherol (vitamin E) induces expression of the vascular endothelial growth factor (VEGF).
 A specific tocopherol and phosphatidylinositol binding protein, hTAP1/SEC14L2, exchanges tocopherol and phosphatidylinositol and modulates their phosphorylation. Lipid binding and exchange by hTAP/SEC14L2 modulates signal transduction and gene expression leading to induction of the expression of VEGF.
A novel signaling pathway involving hTAP1/SEC14L2-mediated lipid exchange lends itself as target for pathogenic and therapeutic studies.
 
Figure Legend
Lipid exchange molecular model for hTAPs and its role in lipid transport and enzyme regulation. (A) hTAPs transfer lipids (e.g. phosphatidylinositol, phosphatidylcholine, vitamin E, squalene) from/to cellular import/export sites or between different membranes and membrane domains such as lipid rafts
. (A and B)
 hTAPs mediated lipid transport may change membrane lipid composition and membrane curvature and in this way influence signal transduction, gene expression and secretion.
 (B) hTAPs bring lipid substrates (S) to specific enzymes (E) (e.g. phosphatidylinositol-3-kinases PI3K , tocopherol kinase, squalene epoxidase), present them in the correct orientation and timing, and/or remove the lipid products (P) from the enzyme, thus enhancing lipid turnover at the catalytic center (CC).
 Lipid release and presentation occurs by lipid exchange with a homotypic or heterotypic lipid and may occur preferentially upon interaction of hTAPs with membranes, thus confining lipid membrane removal/insertion and lipid enzymatic modification to membranes.
 Selected further reading

•  Kempna P, Zingg JM, Ricciarelli R, Hierl M, Saxena S, Azzi A. 2003. Cloning of novel human SEC14p-like proteins: cellular localization, ligand binding and functional properties. Free Radic. Biol. Med. 34:1458-72
• Zingg JM, Azzi A, Meydani M. 2014. Induction of VEGF expression by alpha-tocopherol and alpha-tocopheryl phosphate via PI3Kgamma/PKB and hTAP1/SEC14L2-mediated lipid exchange. J Cell Biochem
• Zingg JM, Libinaki R, Lai CQ, Meydani M, Gianello R, et al. 2010. Modulation of gene expression by alpha-tocopherol and alpha-tocopheryl phosphate in THP-1 monocytes. FRBM 49:1989-2000
• Zingg JM, Meydani M, Azzi A. 2010. alpha-Tocopheryl phosphate – An active lipid mediator? Mol Nutr Food Res 54:1-14
• Zingg JM, Meydani M, Azzi A. 2012. alpha-Tocopheryl phosphate-An activated form of vitamin E important for angiogenesis and vasculogenesis? BioFactors 38:24-33

Journal Reference

Zingg JM¹, Libinaki R², Meydani M¹, Azzi A¹. PLoS One. 2014;9(7):e101550.
¹Vascular Biology Laboratory, JM USDA-Human Nutr. Res. Ctr. On Aging, Tufts University, Boston, Massachusetts, United States of America.and
²Dept. Biochem. and Mol. Biology, Monash University, Melbourne, VIC, Australia.
Abstract

 The vitamin E derivative, alpha-tocopheryl phosphate ({Alpha}TP), is detectable in cultured cells, plasma and tissues in small amounts, suggesting the existence of enzyme(s) with {Alpha}-tocopherol ({Alpha}T) kinase activity. Here, we characterize the production of {Alpha}TP from {Alpha}T and [{Gamma}-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 {Alpha}T, although to a lower amount, also {Gamma}T is phosphorylated. In THP-1 monocytes, {Gamma}TP inhibits cell proliferation and reduces CD36 scavenger receptor expression more potently than {Alpha}TP. Both {Alpha}TP and {Gamma}TP activate the promoter of the human vascular endothelial growth factor (VEGF) gene with similar potency, whereas {Alpha}T and {Gamma}T had no significant effect. The recombinant human tocopherol associated protein 1 (hTAP1, hSEC14L2) binds both {Alpha}T and {Alpha}TP and stimulates phosphorylation of {Alpha}T possibly by facilitating its transport and presentation to a putative {Alpha}T kinase. Recombinant hTAP1 reduces the in vitro activity of the phosphatidylinositol-3-kinase gamma (PI3K{Gamma}) indicating the formation of a stalled/inactive hTAP1/PI3K{Gamma} heterodimer. The addition of {Alpha}T, {Beta}T, {Gamma}T, {delta}T or {Alpha}TP differentially stimulates PI3K{Gamma}, suggesting facilitated egress of sequestered PI from hTAP1 to the enzyme. It is suggested that the continuous competitive exchange of different lipophilic ligands in 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.