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Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1
Huang, Po-Hsien1,2; Chuang, Hsiao-Ching1; Chou, Chih-Chien1; Wang, Huiling1,3; Lee, Su-Lin1; Yang, Hsiao-Ching4; Chiu, Hao-Chieh1; Kapuriya, Naval1; Wang, Dasheng1; Kulp, Samuel K.1; Chen, Ching-Shih1,2
刊名SCIENCE SIGNALING
2013-03-19
DOI10.1126/scisignal.2003816
6期:267
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology ; Cell Biology
资助者NIH grant ; NIH grant
研究领域[WOS]Biochemistry & Molecular Biology ; Cell Biology
关键词[WOS]PLECKSTRIN-HOMOLOGY-DOMAIN ; PROSTATE-CANCER CELLS ; ALPHA-TOCOPHEROL ; LIPID RAFTS ; INHIBITORS ; PTEN ; AKT/PKB ; PATHWAY ; GAMMA ; PHOSPHORYLATION
英文摘要

Vitamin E is a fat-soluble vitamin with antioxidant properties. Tocopherols are the predominant form of vitamin E found in the diet and in supplements and have garnered interest for their potential cancer therapeutic and preventive effects, such as the dephosphorylation of Akt, a serine/threonine kinase with a pivotal role in cell growth, survival, and metabolism. Dephosphorylation of Akt at Ser(473) substantially reduces its catalytic activity and inhibits downstream signaling. We found that the mechanism by which alpha-tocopherol and gamma-tocopherol facilitate this site-specific dephosphorylation of Akt was mediated through the pleckstrin homology (PH) domain-dependent recruitment of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase, isoform 1) to the plasma membrane. We structurally optimized these tocopherols to obtain derivatives with greater in vitro potency and in vivo tumor-suppressive activity in two prostate xenograft tumor models. Binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential recruitment of these proteins to membranes containing tocopherols. Molecular modeling revealed the structural determinants of the interaction with the PH domain of Akt that may inform strategies for continued structural optimization. By describing a mechanism by which tocopherols facilitate the dephosphorylation of Akt at Ser(473), we provide insights into the mode of antitumor action of tocopherols and a rationale for the translational development of tocopherols into novel PH domain-targeted Akt inhibitors.

语种英语
所属项目编号CA112250
资助者NIH grant ; NIH grant
WOS记录号WOS:000316365000004
引用统计
被引频次:23[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/63809
专题北京大学药学院_化学生物学系
作者单位1.Fu Jen Catholic Univ, Dept Chem, New Taipei City 24205, Taiwan
2.Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA
3.Natl Cheng Kung Univ, Inst Basic Med Sci, Tainan 701, Taiwan
4.Peking Univ, Sch Pharmaceut Sci, Dept Biol Chem, Hlth Sci Ctr, Beijing 100191, Peoples R China
推荐引用方式
GB/T 7714
Huang, Po-Hsien,Chuang, Hsiao-Ching,Chou, Chih-Chien,et al. Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1[J]. SCIENCE SIGNALING,2013,6(267).
APA Huang, Po-Hsien.,Chuang, Hsiao-Ching.,Chou, Chih-Chien.,Wang, Huiling.,Lee, Su-Lin.,...&Chen, Ching-Shih.(2013).Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1.SCIENCE SIGNALING,6(267).
MLA Huang, Po-Hsien,et al."Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1".SCIENCE SIGNALING 6.267(2013).
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