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Identification of an AMPK Phosphorylation Site in Drosophila TSC2 (gigas) that Regulate Cell Growth

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
Author to whom correspondence should be addressed.
Academic Editor: Alan C. Leonard
Int. J. Mol. Sci. 2015, 16(4), 7015-7026;
Received: 6 March 2015 / Revised: 19 March 2015 / Accepted: 23 March 2015 / Published: 27 March 2015
(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)
AMP-activated protein kinase (AMPK) is an important metabolic regulator that mediates cellular adaptation to diverse stresses. One of the AMPK substrates, tuberous sclerosis complex 2 (TSC2), was suggested to mediate AMPK-induced silencing of mTOR complex 1 (mTORC1) signaling that is critical for cell growth. However, it is not known whether the AMPK-dependent TSC2 phosphorylation, originally observed in mammalian cells, is conserved in invertebrates. Here we show that energy depletion inhibits mTORC1 signaling through the AMPK-TSC2 axis in Drosophila S2 cells. We have discovered an AMPK phosphorylation site in TSC2-like genes from many different invertebrate species including Drosophila. The site (Ser1338 in Drosophila TSC2) is specifically and efficiently phosphorylated by AMPK in vitro. To evaluate the functional role of this phosphorylation site in vivo, we generated transgenic flies that can express identical amount of either wild-type or phosphorylation-resistant mutant Drosophila TSC2 in a tissue-specific manner. In response to transgenic Sestrin induction, which causes ectopic AMPK activation and subsequent mTORC1 inhibition, wild-type Drosophila TSC2 synergistically reduced tissue growth in the dorsal epithelium of Drosophila wings. However, phosphorylation-resistant mutant Drosophila TSC2 was unable to show such a growth-inhibiting effect, suggesting that this phosphorylation is important for AMPK-dependent regulation of cell growth. View Full-Text
Keywords: Drosophila; AMPK; mTOR; mTORC1; TSC2 Drosophila; AMPK; mTOR; mTORC1; TSC2
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Kim, M.; Lee, J.H. Identification of an AMPK Phosphorylation Site in Drosophila TSC2 (gigas) that Regulate Cell Growth. Int. J. Mol. Sci. 2015, 16, 7015-7026.

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