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Molecular and Cellular Biology, October 2004, p. 8778-8789, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8778-8789.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Protein Phosphatase 2A Negatively Regulates Insulin's Metabolic Signaling Pathway by Inhibiting Akt (Protein Kinase B) Activity in 3T3-L1 Adipocytes

Satoshi Ugi,1 Takeshi Imamura,2 Hiroshi Maegawa,1 Katsuya Egawa,1 Takeshi Yoshizaki,1 Kun Shi,1 Toshiyuki Obata,3 Yousuke Ebina,3 Atsunori Kashiwagi,1 and Jerrold M. Olefsky2*

Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga,1 Division of Molecular Genetics, Institutes for Enzyme Research, Graduate School of Medicine, University of Tokushima, Kuramoto, Tokushima, Japan,3 Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, The Hillblom Diabetes Center, and The Whittier Diabetes Institute, La Jolla, California2

Received 14 November 2003/ Returned for modification 16 February 2004/ Accepted 22 June 2004

Protein phosphatase 2A (PP2A) is a multimeric serine/threonine phosphatase which has multiple functions, including inhibition of the mitogen-activated protein (MAP) kinase pathway. Simian virus 40 small t antigen specifically inhibits PP2A function by binding to the PP2A regulatory subunit, interfering with the ability of PP2A to associate with its cellular substrates. We have reported that the expression of small t antigen inhibits PP2A association with Shc, leading to augmentation of insulin and epidermal growth factor-induced Shc phosphorylation with enhanced activation of the Ras/MAP kinase pathway. However, the potential involvement of PP2A in insulin's metabolic signaling pathway is presently unknown. To assess this, we overexpressed small t antigen in 3T3-L1 adipocytes by adenovirus-mediated gene transfer and found that the phosphorylation of Akt and its downstream target, glycogen synthase kinase 3ß, were enhanced both in the absence and in the presence of insulin. Furthermore, protein kinase C {lambda} (PKC {lambda}) activity was also augmented in small-t-antigen-expressing 3T3-L1 adipocytes. Consistent with this result, both basal and insulin-stimulated glucose uptake were enhanced in these cells. In support of this result, when inhibitory anti-PP2A antibody was microinjected into 3T3-L1 adipocytes, we found a twofold increase in GLUT4 translocation in the absence of insulin. The small-t-antigen-induced increase in Akt and PKC {lambda} activities was not inhibited by wortmannin, while the ability of small t antigen to enhance glucose transport was inhibited by dominant negative Akt (DN-Akt) expression and Akt small interfering RNA (siRNA) but not by DN-PKC {lambda} expression or PKC {lambda} siRNA. We conclude that PP2A is a negative regulator of insulin's metabolic signaling pathway by promoting dephosphorylation and inactivation of Akt and PKC {lambda} and that most of the effects of PP2A to inhibit glucose transport are mediated through Akt.

* Corresponding author. Mailing address: Department of Medicine (0673), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0673. Phone: (858) 534-6651. Fax: (858) 534-6653. E-mail: jolefsky{at}ucsd.edu.

Molecular and Cellular Biology, October 2004, p. 8778-8789, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8778-8789.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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