Vitamin e facilitates the inactivation of the kinase akt by the phosphatase PHLPP1

Po-Hsien Huang, Hsiao Ching Chuang, Chih Chien Chou, Huiling Wang, Su Lin Lee, Hsiao Ching Yang, Hao Chieh Chiu, Naval Kapuriya, Dasheng Wang, Samuel K. Kulp, Ching Shih Chen

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 Ser473 substantially reduces its catalytic activity and inhibits downstream signaling. We found that the mechanism by which a-tocopherol and g-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 Ser473, 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.

Original languageEnglish
JournalScience Signaling
Volume6
Issue number267
DOIs
Publication statusPublished - 2013 Mar 19

Fingerprint

Tocopherols
Phosphoric Monoester Hydrolases
Vitamins
Phosphotransferases
Vitamin E
Tumors
Protein Phosphatase 1
Neoplasms
Molecular modeling
Structural optimization
Phosphoprotein Phosphatases
Protein-Serine-Threonine Kinases
Cell growth
Therapeutic Uses
Cell membranes
Nutrition
Heterografts
Metabolism
platelet protein P47
Pleckstrin Homology Domains

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Huang, P-H., Chuang, H. C., Chou, C. C., Wang, H., Lee, S. L., Yang, H. C., ... Chen, C. S. (2013). Vitamin e facilitates the inactivation of the kinase akt by the phosphatase PHLPP1. Science Signaling, 6(267). https://doi.org/10.1126/scisignal.2003816
Huang, Po-Hsien ; Chuang, Hsiao Ching ; Chou, Chih Chien ; Wang, Huiling ; Lee, Su Lin ; Yang, Hsiao Ching ; Chiu, Hao Chieh ; Kapuriya, Naval ; Wang, Dasheng ; Kulp, Samuel K. ; Chen, Ching Shih. / Vitamin e facilitates the inactivation of the kinase akt by the phosphatase PHLPP1. In: Science Signaling. 2013 ; Vol. 6, No. 267.
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Huang, P-H, Chuang, HC, Chou, CC, Wang, H, Lee, SL, Yang, HC, Chiu, HC, Kapuriya, N, Wang, D, Kulp, SK & Chen, CS 2013, 'Vitamin e facilitates the inactivation of the kinase akt by the phosphatase PHLPP1', Science Signaling, vol. 6, no. 267. https://doi.org/10.1126/scisignal.2003816

Vitamin e facilitates the inactivation of the kinase akt by the phosphatase PHLPP1. / Huang, Po-Hsien; Chuang, Hsiao Ching; Chou, Chih Chien; Wang, Huiling; Lee, Su Lin; Yang, Hsiao Ching; Chiu, Hao Chieh; Kapuriya, Naval; Wang, Dasheng; Kulp, Samuel K.; Chen, Ching Shih.

In: Science Signaling, Vol. 6, No. 267, 19.03.2013.

Research output: Contribution to journalArticle

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AU - Huang, Po-Hsien

AU - Chuang, Hsiao Ching

AU - Chou, Chih Chien

AU - Wang, Huiling

AU - Lee, Su Lin

AU - Yang, Hsiao Ching

AU - Chiu, Hao Chieh

AU - Kapuriya, Naval

AU - Wang, Dasheng

AU - Kulp, Samuel K.

AU - Chen, Ching Shih

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N2 - 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 Ser473 substantially reduces its catalytic activity and inhibits downstream signaling. We found that the mechanism by which a-tocopherol and g-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 Ser473, 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.

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