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Molecular and Cellular Biology, January 2008, p. 61-70, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01405-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Muscle-Specific Deletion of Rictor Impairs Insulin-Stimulated Glucose Transport and Enhances Basal Glycogen Synthase Activity{triangledown}

Anil Kumar,1* Thurl E. Harris,1 Susanna R. Keller,2 Kin M. Choi,1,{dagger} Mark A. Magnuson,3 and John C. Lawrence Jr.1,{ddagger}

Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia 22908,1 Internal Medicine, Division of Endocrinology, University of Virginia Health System, Charlottesville, Virginia 22908,2 Center for Stem Cell Biology and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 372323

Received 5 August 2007/ Returned for modification 31 August 2007/ Accepted 16 October 2007

Rictor is an essential component of mTOR (mammalian target of rapamycin) complex 2 (mTORC2), a kinase complex that phosphorylates Akt at Ser473 upon activation of phosphatidylinositol 3-kinase (PI-3 kinase). Since little is known about the role of either rictor or mTORC2 in PI-3 kinase-mediated physiological processes in adult animals, we generated muscle-specific rictor knockout mice. Muscle from male rictor knockout mice exhibited decreased insulin-stimulated glucose uptake, and the mice showed glucose intolerance. In muscle lacking rictor, the phosphorylation of Akt at Ser473 was reduced dramatically in response to insulin. Furthermore, insulin-stimulated phosphorylation of the Akt substrate AS160 at Thr642 was reduced in rictor knockout muscle, indicating a defect in insulin signaling to stimulate glucose transport. However, the phosphorylation of Akt at Thr308 was normal and sufficient to mediate the phosphorylation of glycogen synthase kinase 3 (GSK-3). Basal glycogen synthase activity in muscle lacking rictor was increased to that of insulin-stimulated controls. Consistent with this, we observed a decrease in basal levels of phosphorylated glycogen synthase at a GSK-3/protein phosphatase 1 (PP1)-regulated site in rictor knockout muscle. This change in glycogen synthase phosphorylation was associated with an increase in the catalytic activity of glycogen-associated PP1 but not increased GSK-3 inactivation. Thus, rictor in muscle tissue contributes to glucose homeostasis by positively regulating insulin-stimulated glucose uptake and negatively regulating basal glycogen synthase activity.

* Corresponding author. Mailing address: Department of Pharmacology, University of Virginia Health System, P.O. Box 800735, 1300 Jefferson Park Ave., Charlottesville, VA 22908. Phone: (434) 924-1582. Fax: (434) 982-3878. E-mail: al4p{at}virginia.edu

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Present address: Primanova Biosciences, Inc., 3235 Route 112, Medford, NY 11763.

{ddagger} Died on 19 December 2006.

Molecular and Cellular Biology, January 2008, p. 61-70, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01405-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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