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PMID: 19446321 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.

Cell ·Vol. 137 ·No. 5 ·2009-05-29 ·Pages 873-86

Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM

Abstract

The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.

MeSH Terms
Cell Line Cell Survival Cyclin D1/metabolism Cyclin D3 Cyclins/metabolism Humans Intracellular Signaling Peptides and Proteins Multiple Myeloma/metabolism Phosphatidylinositol 3-Kinases/metabolism Protein Kinases/metabolism Proto-Oncogene Proteins c-akt/metabolism Signal Transduction TOR Serine-Threonine Kinases/metabolism
Chemicals
CCND3 protein, human Cyclin D3 Cyclins Intracellular Signaling Peptides and Proteins Cyclin D1 Protein Kinases DEPTOR protein, human MTOR protein, human Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Peterson Timothy R
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
Laplante Mathieu
Thoreen Carson C
Sancak Yasemin
Kang Seong A
Kuehl W Michael
Gray Nathanael S
Sabatini David M
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2009.03.046
Published
2009-05-29
Epub
2009-00-14
Pages
873-86
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2758791
Subset
IM
Grants
NIAID NIH HHS · R01 AI47389 · United States
NIAID NIH HHS · R01 AI047389-07 · United States
NCI NIH HHS · R01 CA103866-03 · United States
NIAID NIH HHS · R01 AI047389-08 · United States
Intramural NIH HHS · United States
NCI NIH HHS · R01 CA129105 · United States
NIAID NIH HHS · R01 AI047389-09 · United States
NIAID NIH HHS · R01 AI047389 · United States
NCI NIH HHS · R01 CA103866 · United States
NIAID NIH HHS · R01 AI047389-10 · United States
NCI NIH HHS · R01 CA103866-02 · United States
NCI NIH HHS · R01 CA103866-05 · United States
NCI NIH HHS · R01 CA103866-04 · United States
NCI NIH HHS · R01 CA103866-01 · United States
NCI NIH HHS · R01 CA129105-03 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2009.03.046 PMC Full Text View journal details
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