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Molecular and Cellular Biology, September 2006, p. 6425-6434, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.01254-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Turnover of the Active Fraction of IRS1 Involves Raptor-mTOR- and S6K1-Dependent Serine Phosphorylation in Cell Culture Models of Tuberous Sclerosis

O. Jameel Shah1,2 and Tony Hunter1*

Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037,1 Abbott Laboratories, Global Pharmaceutical Research and Development, Cancer Biology Division, 100 Abbott Park Road, Abbott Park, Illinois 600642

Received 2 July 2005/ Returned for modification 17 August 2005/ Accepted 12 June 2006

The TSC1-TSC2/Rheb/Raptor-mTOR/S6K1 cell growth cassette has recently been shown to regulate cell autonomous insulin and insulin-like growth factor I (IGF-I) sensitivity by transducing a negative feedback signal that targets insulin receptor substrates 1 and 2 (IRS1 and -2). Using two cell culture models of the familial hamartoma syndrome, tuberous sclerosis, we show here that Raptor-mTOR and S6K1 are required for phosphorylation of IRS1 at a subset of serine residues frequently associated with insulin resistance, including S307, S312, S527, S616, and S636 (of human IRS1). Using loss- and gain-of-function S6K1 constructs, we demonstrate a requirement for the catalytic activity of S6K1 in both direct and indirect regulation of IRS1 serine phosphorylation. S6K1 phosphorylates IRS1 in vitro on multiple residues showing strong preference for RXRXXS/T over S/T,P sites. IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb. These studies suggest that, through serine phosphorylation, Raptor-mTOR and S6K1 cell autonomously promote the depletion of IRS1 from specific intracellular pools in pathological states of insulin and IGF-I resistance and thus potentially in lesions associated with tuberous sclerosis.

* Corresponding author. Mailing address: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 453-4100, ext. 1385. Fax: (858) 457-4765. E-mail: hunter{at}salk.edu.

Molecular and Cellular Biology, September 2006, p. 6425-6434, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.01254-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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