Journal
JOURNAL OF CELL BIOLOGY
Volume 173, Issue 2, Pages 279-289Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200507119
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Funding
- NCI NIH HHS [R01 CA063613, P30 CA016672, CA63613, CA16672] Funding Source: Medline
- NICHD NIH HHS [R01 HD046282, HD46282] Funding Source: Medline
- NIEHS NIH HHS [ES07784, R01 ES008263, P30 ES007784, ES08263-06S1] Funding Source: Medline
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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 co-localizes 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.
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