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Journal of Biochemistry Advance Access originally published online on July 15, 2009
Journal of Biochemistry 2009 146(4):541-547; doi:10.1093/jb/mvp104
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© The Authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

Membrane Localization of Protein-Tyrosine Phosphatase 1B is Essential for its Activation of Sterol Regulatory Element-Binding Protein-1 Gene Expression and Consequent Hypertriglyceridaemia

Satoshi Ugi1,*,{dagger}, Kun Shi1,2,{dagger}, Yoshihiko Nishio1, Shinya Shimizu1, Baoliang Guo1, Osamu Sekine1, Kazuhiro Ikeda1, Katsuya Egawa1, Takeshi Yoshizaki1, Yoshio Nagai1, Daisuke Koya1, Tatsuyuki Takada3, Ryozo Torii3, Hiroshi Kimura4, Atsunori Kashiwagi1 and Hiroshi Maegawa1

1Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan; 2Department of Gynecology and Obstetrics, Harbin Medical University, Harbin 150086, China; 3Research Center for Animal Life Science; and 4Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan

*To whom correspondence should be addressed. Tel: +81-77-548-2223, Fax: +81-77-543-3858, E-mail: sugi{at}belle.shiga-med.ac.jp

Received March 30, 2009; Accepted June 18, 2009


  Abstract

Protein-tyrosine phosphatase 1B (PTP1B) is a major regulator of insulin sensitivity. We have described a novel action of PTP1B in the induction of sterol regulatory element-binding protein-1 (SREBP-1) gene expression through activation of protein phosphatase 2A (PP2A). PTP1B is anchored to the endoplasmic reticulum membrane via its C-terminal tail. We have previously reported that membrane localization of PTP1B is essential for PP2A activation, which is crucial for enhancing SREBP-1 gene expression in in vitro experiments. In this study, we further investigated the physiological importance of membrane localization of PTP1B in vivo. We found that transient liver-specific overexpression of wild-type PTP1B (PTP1B-WT) using adenovirus-mediated gene transfer was associated with hypertriglyceridaemia and enhanced hepatic SREBP-1 gene expression in mice. However, overexpression of the C-terminal truncated PTP1B (PTP1B{Delta}CT) failed to increase hepatic SREBP-1 expression or serum triglyceride levels, despite causing insulin resistance. Our results indicate that activation of PTP1B in the liver could induce hypertriglyceridaemia and that anchoring of PTP1B to the membrane is crucial for its action.

Key Words: endoplasmic reticulum, protein phosphatase 2A, protein-tyrosine phosphatase 1B, sterol regulatory element-binding protein-1

Abbreviations: ER, endoplasmic reticulum; G6Pase, glucose 6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; p-NPP, para-nitrophenyl phosphate; PP2A, protein phosphatase 2A; PTP1B, protein-tyrosine phosphatase 1B; PTP1B{Delta}CT, C-terminal-truncated PTP1B; PTP1B{Delta}CT-CAAX, membrane-targeted PTP1B{Delta}CT; SREBP, sterol regulatory element-binding protein; WT, wild-type

{dagger}These two authors contributed equally to this work.


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