TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.

By K. Inoki, H. Ouyang, Tianqing Zhu, Charlotta Lindvall, Yian Wang, Xiaojie Zhang, Qian Yang, C. Bennett, Y. Harada, Kryn Stankunas and 6 more. Cell, 2006

1,421 citations recorded by the source corpus.

Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/2168f52d04ad2def712991ee5d147b17cd47bf73

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Citations in the corpus

The LKB1-AMPK pathway: metabolism and growth control in tumor suppression (2009, background): “and primes serine residues close to these conserved sites for subsequent phosphorylation by glycogen synthase kinase 3 (GSK3”
Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases (2011, background): “The and isoforms of p38 are in parentheses to indicate that they have not been shown to promote MAPKAPK activation. on M arch 26, 2021 by guest http://m m br.asm .org/ D ow nloaded from protein kinase [DAPK], tuberous sclerosis complex 2 [TSC2], RSK, and MNK) and the nucleus (NF-AT, Elk-1, myocyte e”
Amino acid signalling upstream of mTOR (2013, neutral): “metabolism by the PI(3)K–PKB–FOXO network regulates autophagy.”
Regulation of Immune Responses by mTOR (2011, background): “Likewise, phosphorylation of TSC by glycogen synthase kinase 3β (GSK3β) also inhibits mTOR (31).”
Defining the role of mTOR in cancer. (2007, background): “In contrast to growth-factor-driven activation of mTORC1, hypoxia, AMPK activation resulting from depletion of cellular energy, WNT-GSK3 signaling, and glucocorticoids all inhibit mTORC1 by promoting TSC1/2 activation (Inoki et al., 2006; Reiling and Sabatini, 2006; Wang et al., 2006).”
mTOR signaling in growth control and disease (2012, positive): “In this case, Wnt signaling inhibits glycogen synthase kinase 3b (GSK3-b), which normally phosphorylates and promotes TSC2 activity (Inoki et al., 2006).”
mTOR: from growth signal integration to cancer, diabetes and ageing (2010, background): “Moreover, the Wnt pathway has been implicated in mTORC1 signallin”
mTOR signaling at a glance (2009, background): “Stimulation of the Wnt pathway inhibits glycogen synthase kinase 3 (GSK3), a kinase that promotes TSC1/2 activity by directly phosphorylating TSC2 (Inoki et al., 2006).”
With TOR less is more: a key role for the conserved nutrient sensing TOR pathway in aging (2010, positive): “When active, Gsk3 has been shown to directly phosphorylate and activate Tsc2 when primed by AMPK-dependent phosphorylation (Inoki et al., 2006).”