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

Sheng Li Cai, Andrew R. Tee, John D. Short, Judith M. Bergeron, Jinhee Kim, Jianjun Shen, Ruifeng Guo, Charles L. Johnson, Kaoru Kiguchi, Cheryl Lyn Walker

Research output: Contribution to journalArticle

244 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)279-289
Number of pages11
JournalJournal of Cell Biology
Volume173
Issue number2
DOIs
StatePublished - Apr 24 2006

ASJC Scopus subject areas

  • Cell Biology

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