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

Ken Inoki; Hongjiao Ouyang; Tianqing Zhu; Charlotta Lindvall; Yian Wang; Xiaojie Zhang; Qian Yang; Christina Bennett; Yuko Harada; Kryn Stankunas; Cun yu Wang; Xi He; Ormond A. MacDougald; Ming You; Bart O. Williams; Kun Liang Guan

doi:10.1016/j.cell.2006.06.055

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

Ken Inoki, Hongjiao Ouyang, Tianqing Zhu, Charlotta Lindvall, Yian Wang, Xiaojie Zhang, Qian Yang, Christina Bennett, Yuko Harada, Kryn Stankunas, Cun yu Wang, Xi He, Ormond A. MacDougald, Ming You, Bart O. Williams, Kun Liang Guan

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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 β-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.

Original language	English (US)
Pages (from-to)	955-968
Number of pages	14
Journal	Cell
Volume	126
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2006.06.055
State	Published - Sep 8 2006

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2006.06.055

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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. (2006). TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth. Cell, 126(5), 955-968. https://doi.org/10.1016/j.cell.2006.06.055

Inoki, K, Ouyang, H, Zhu, T, Lindvall, C, Wang, Y, Zhang, X, Yang, Q, Bennett, C, Harada, Y, Stankunas, K, Wang, CY, He, X, MacDougald, OA, You, M, Williams, BO & Guan, KL 2006, 'TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth', Cell, vol. 126, no. 5, pp. 955-968. https://doi.org/10.1016/j.cell.2006.06.055

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

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 β-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.",

author = "Ken Inoki and Hongjiao Ouyang and Tianqing Zhu and Charlotta Lindvall and Yian Wang and Xiaojie Zhang and Qian Yang and Christina Bennett and Yuko Harada and Kryn Stankunas and Wang, {Cun yu} and Xi He and MacDougald, {Ormond A.} and Ming You and Williams, {Bart O.} and Guan, {Kun Liang}",

note = "Funding Information: We thank Drs. Eric Fearon, Yue Xiong, and Martha Somerman for providing reagents and cells and Cassandra Zylstra for technical assistance. We also thank Huira Chong, Michael N. Corradetti, and Chung-Han Lee for critical reading of the manuscript. This work is supported by grants from NIH (K.-L.G, H.O, and C.-Y.W.), American Association of Endodontics (H.O.), and Michigan Cancer Center and Diabetic Center (K.-L.G). ",

year = "2006",

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doi = "10.1016/j.cell.2006.06.055",

language = "English (US)",

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AU - Inoki, Ken

AU - Ouyang, Hongjiao

AU - Zhu, Tianqing

AU - Lindvall, Charlotta

AU - Wang, Yian

AU - Zhang, Xiaojie

AU - Yang, Qian

AU - Bennett, Christina

AU - Harada, Yuko

AU - Stankunas, Kryn

AU - Wang, Cun yu

AU - He, Xi

AU - MacDougald, Ormond A.

AU - You, Ming

AU - Williams, Bart O.

AU - Guan, Kun Liang

N1 - Funding Information: We thank Drs. Eric Fearon, Yue Xiong, and Martha Somerman for providing reagents and cells and Cassandra Zylstra for technical assistance. We also thank Huira Chong, Michael N. Corradetti, and Chung-Han Lee for critical reading of the manuscript. This work is supported by grants from NIH (K.-L.G, H.O, and C.-Y.W.), American Association of Endodontics (H.O.), and Michigan Cancer Center and Diabetic Center (K.-L.G).

PY - 2006/9/8

Y1 - 2006/9/8

N2 - 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 β-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.

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

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