Phosphatidic acid activates mammalian target of rapamycin complex 1 (mTORC1) kinase by displacing FK506 binding protein 38 (FKBP38) and exerting an allosteric effect

Mee Sup Yoon, Yuting Sun, Edwin Arauz, Yu Jiang, Jie Chen

Research output: Contribution to journalArticle

Abstract

Phosphatidic acid (PA) is a critical mediator of mitogenic activation of mammalian target of rapamycin complex 1 (mTORC1) signaling, a master regulator of mammalian cell growth and proliferation. The mechanism by which PA activates mTORC1 signaling has remained unknown. Here, we report that PA selectively stimulates mTORC1 but not mTORC2 kinase activity in cells and in vitro. Furthermore, we show that PA competes with them TORC1 inhibitor, FK506 binding protein 38 (FKBP38), for mTOR binding at a site encompassing the rapamycin-FKBP12 binding domain. This leads to PA antagonizing FKBP38 inhibition of mTORC1 kinase activity in vitro and rescuing mTORC1 signaling from FKBP38 in cells. Phospholipase D 1, a PA-generating enzyme that is an established upstream regulator of mTORC1, is found to negatively affect mTOR-FKBP38 interaction, confirming the role of endogenous PA in this regulation. Interestingly, removal of FKBP38 alone is insufficient to activate mTORC1 kinase and signaling, which require PA even when the FKBP38 level is drastically reduced by RNAi. In conclusion, we propose a dual mechanism for PA activation of mTORC1: PA displaces FKBP38 from mTOR and allosterically stimulates the catalytic activity of mTORC1.

Original languageEnglish (US)
Pages (from-to)29568-29574
Number of pages7
JournalJournal of Biological Chemistry
Volume286
Issue number34
DOIs
StatePublished - Aug 26 2011

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Tacrolimus Binding Proteins
Phosphatidic Acids
Phosphotransferases
Tacrolimus Binding Protein 1A
Chemical activation
mechanistic target of rapamycin complex 1
Phospholipase D
Cell proliferation
Cell growth
Sirolimus
RNA Interference
Catalyst activity
Cell Proliferation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Phosphatidic acid activates mammalian target of rapamycin complex 1 (mTORC1) kinase by displacing FK506 binding protein 38 (FKBP38) and exerting an allosteric effect. / Yoon, Mee Sup; Sun, Yuting; Arauz, Edwin; Jiang, Yu; Chen, Jie.

In: Journal of Biological Chemistry, Vol. 286, No. 34, 26.08.2011, p. 29568-29574.

Research output: Contribution to journalArticle

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