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PMID: 25936805 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid.

Molecular cell ·Vol. 58 ·No. 3 ·2015-05-07 ·Pages 549-56

Yoon MS, Rosenberger CL, Wu C, Truong N, Sweedler JV, Chen J

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen-stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product phosphatidic acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function.

MeSH Terms
3T3 Cells Animals Binding, Competitive/drug effects Blotting, Western Cell Line Culture Media/pharmacology HEK293 Cells HeLa Cells Humans Insulin/pharmacology Intracellular Signaling Peptides and Proteins/genetics,metabolism Mass Spectrometry Mechanistic Target of Rapamycin Complex 1 Mice Mitogens/metabolism,pharmacology Multiprotein Complexes/genetics,metabolism Phosphatidic Acids/metabolism,pharmacology Phospholipase D/metabolism Protein Binding/drug effects RNA Interference Serum TOR Serine-Threonine Kinases/genetics,metabolism Tetradecanoylphorbol Acetate/pharmacology
Chemicals
Culture Media Insulin Intracellular Signaling Peptides and Proteins Mitogens Multiprotein Complexes Phosphatidic Acids DEPTOR protein, human MTOR protein, human Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases Phospholipase D Tetradecanoylphorbol Acetate
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Yoon Mee-Sup
Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA; Department of Molecular Medicine, Graduate School of Medicine, Gachon University, Incheon 406-840, Republic of Korea. Electronic address: msyoon@gachon.ac.kr.
Rosenberger Christina L
Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
Wu Cong
Departments of Chemistry and Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
Truong Nga
Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
Sweedler Jonathan V
Departments of Chemistry and Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
Chen Jie
Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: jiechen@illinois.edu.
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2015.03.028
Email
msyoon@gachon.ac.kr
jiechen@illinois.edu
Published
2015-05-07
Epub
2015-00-30
Pages
549-56
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC4427522
Subset
IM
Grants
NIDA NIH HHS · P30 DA018310 · United States
NIAMS NIH HHS · R01 AR048914 · United States
NIGMS NIH HHS · R01 GM089771 · United States
NIGMS NIH HHS · GM089771 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2015.03.028 PMC Full Text View journal details
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