Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons

Sun Gyun Kim, Suho Lee, Yangsik Kim, Jieun Park, Doyeon Woo, Dayeon Kim, Yan Li, Wangyong Shin, Hyunjeong Kang, Chaehyun Yook, Minji Lee, Kyungdeok Kim, Junyeop Daniel Roh, Jeseung Ryu, Hwajin Jung, Seung Min Um, Esther Yang, Hyun Kim, Jinju Han, Won Do HeoEunjoon Kim

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.

Original languageEnglish
Article number2695
JournalNature communications
Issue number1
Publication statusPublished - 2021 Dec 1

Bibliographical note

Funding Information:
We would like to Dr Kwang-Wook Choi in the Department of Biological Sciences at KAIST for thoughtful comments on the manuscript. This work was supported by the Ministry of Health & Welfare (HI18C1077 to J.H.), NRF Grant 2017M3C7A1079692 (to H.K.), and the Institute for Basic Science (IBS-R002-A1 to J.H. and IBS-R002-D1 to E.K.).

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General
  • General Physics and Astronomy


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