Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly

Takeshi Kaizuka, Taichi Hara, Noriko Oshiro, Ushio Kikkawa, Kazuyoshi Yonezawa, Kenji Takehana, Shun Ichiro Iemura, Tohru Natsume, Noboru Mizushima

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

Mammalian target of rapamycin (mTOR) is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family and is a major regulator of translation, cell growth, and autophagy. mTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. S. pombe Tti1 binds to Tel2, a protein whose mammalian homolog was recently reported to regulate the stability of PIKKs. We confirmed that Tti1 binds to Tel2 also in mammalian cells, and Tti1 interacts with and stabilizes all six members of the PIKK family of proteins (mTOR, ATM, ATR, DNA-PKcs, SMG-1, and TRRAP). Furthermore, using immuno-precipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. These results indicate that Tti1 and Tel2 are important not only for mTOR stability but also for assembly of the mTOR complexes to maintain their activities.

Original languageEnglish
Pages (from-to)20109-20116
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number26
DOIs
Publication statusPublished - 2010 Jun 25
Externally publishedYes

Fingerprint

Sirolimus
TOR Serine-Threonine Kinases
Phosphatidylinositol 3-Kinase
Schizosaccharomyces
Autophagy
Phosphotransferases
Sequence Homology
Gel Chromatography
Phosphorylation
Proteins
Size exclusion chromatography
Automatic teller machines
Cell growth
Substrates
mechanistic target of rapamycin complex 1
TOR complex 2
DNA
Cells
Growth
Chemical analysis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Kaizuka, T., Hara, T., Oshiro, N., Kikkawa, U., Yonezawa, K., Takehana, K., ... Mizushima, N. (2010). Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. Journal of Biological Chemistry, 285(26), 20109-20116. https://doi.org/10.1074/jbc.M110.121699

Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. / Kaizuka, Takeshi; Hara, Taichi; Oshiro, Noriko; Kikkawa, Ushio; Yonezawa, Kazuyoshi; Takehana, Kenji; Iemura, Shun Ichiro; Natsume, Tohru; Mizushima, Noboru.

In: Journal of Biological Chemistry, Vol. 285, No. 26, 25.06.2010, p. 20109-20116.

Research output: Contribution to journalArticle

Kaizuka, T, Hara, T, Oshiro, N, Kikkawa, U, Yonezawa, K, Takehana, K, Iemura, SI, Natsume, T & Mizushima, N 2010, 'Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly', Journal of Biological Chemistry, vol. 285, no. 26, pp. 20109-20116. https://doi.org/10.1074/jbc.M110.121699
Kaizuka, Takeshi ; Hara, Taichi ; Oshiro, Noriko ; Kikkawa, Ushio ; Yonezawa, Kazuyoshi ; Takehana, Kenji ; Iemura, Shun Ichiro ; Natsume, Tohru ; Mizushima, Noboru. / Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 26. pp. 20109-20116.
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