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Published 24 April 2006. doi:10.1083/jcb.200507119
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 2, 279-289
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Article

Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning



Sheng-Li Cai1, Andrew R. Tee2, John D. Short1, Judith M. Bergeron1, Jinhee Kim1, Jianjun Shen1, Ruifeng Guo1, Charles L. Johnson1, Kaoru Kiguchi1, and Cheryl Lyn Walker1

1 Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957
2 Division of Molecular Physiology, University of Dundee, Medical Sciences Institute/Wellcome Building Complex, Dundee DD1 5EH, Scotland, UK

Correspondence to Cheryl Lyn Walker: cwalker{at}wotan.mdacc.tmc.edu

Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that hamartin colocalizes with hypophosphorylated tuberin at the membrane, where tuberin exerts its GTPase-activating protein (GAP) activity to repress Rheb signaling. In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 14-3-3 in response to AKT phosphorylation is sequestered away from its membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to relieve the growth inhibitory effects of this tumor suppressor.

Abbreviations used in this paper: CIAP, calf intestinal alkaline phosphatase; GAP, GTPase-activating protein; IGF-1, insulin-like growth factor-1; mTOR, mammalian TOR; PI3K, phosphoinositide 3-kinase; Rheb, Ras homologue enriched in brain; RSK, ribosomal S6K; S6K, S6 kinase; TOR, target of rapamycin; TSC, tuberous sclerosis complex.


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