Cited by 1,377PI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex ResearchWnt/β-catenin signaling in development and cancer

TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth

Open access
Inoki, Ken, Ouyang, Hongjiao, Zhu, Tianqing, Lindvall, Charlotta, Wang, Yian, Zhang, Xiaojie, Yang, Qian, Bennett, Christina +8 more·2006·Cell

Abstract

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.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2006.06.055

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53 of 53 references verified0 citation errors · 0 not checkable

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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
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
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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