TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth
Open accessAbstract
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.
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For cell growth, Wnt signaling via Dsh and GSK3 regulates the TSC2 tumor suppressor to negatively regulate mTor.
“For cell growth, Wnt signaling via Dsh and GSK3 regulates the TSC2 tumor suppressor to negatively regulate mTor.108,109”
From Wnt signal transduction pathways (2008) · cites this paper as [109]
Activation of mTOR signaling is linked to deactivation of the serine/threonine kinase GSK-3.
“Activation of mTOR signaling is linked to deactivation of the serine/threonine kinase glycogen synthase kinase-3 (GSK-3).”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [184]
Upstream phosphorylation (deactivation) of GSK-3 induces mTOR activation.
“In particular, upstream phosphorylation (deactivation) of GSK-3 induces mTOR activation (see Figure 1) 184, 185.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [184]
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- Authors
- Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., Yang, Q., Bennett, C., Harada, Y., Stankunas, K., Wang, C.-Y., He, X., MacDougald, O. A., You, M., Williams, B. O., & Guan, K.-L.
- Affiliations
- University of Michigan (US)
- Van Andel Institute (US)
- Washington University in St. Louis (US)
- Boston Children's Hospital (US)
- Stanford Medicine (US)
- Corresponding author
- Guan, Kun-Liang
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 126
- Issue
- 5
- Pages
- 955-968
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2018553282
- Cited by
- 1,377
- References
- 53
- Citations by year
- 2026: 33 · 2025: 47 · 2024: 53 · 2023: 56 · 2022: 64 · 2021: 96 · 2020: 86 · 2019: 62 · 2018: 73 · 2017: 82 · 2016: 77 · 2015: 79 · 2014: 98 · 2013: 84 · 2012: 80
- FWCI
- 19.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2547 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R21CA161150)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124709)
- National Institute of Dental and Craniofacial Research (R01DE017439)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- TSC2, Wnt signaling, AMPK, glycogen synthase kinase-3, mTOR, cell growth regulation, tuberous sclerosis complex, Rheb, GTPase-activating protein, rapamycin, signal integration, phosphorylation, translation (biology), tumor suppressor
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, Animals, Antibiotics, Antineoplastic, Cell Transformation, Neoplastic, Humans, Mammary Neoplasms, Experimental, Multienzyme Complexes, Mutation, Phosphorylation, Protein Kinases, Transfection, Signal Transduction, Protein Serine-Threonine Kinases, Sirolimus, Tumor Suppressor Proteins, Glycogen Synthase Kinase 3, Cell Line, Tumor, Cell Proliferation, Wnt Proteins, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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