TY - JOUR
T1 - DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival
AU - Peterson, Timothy R.
AU - Laplante, Mathieu
AU - Thoreen, Carson C.
AU - Sancak, Yasemin
AU - Kang, Seong A.
AU - Kuehl, W. Michael
AU - Gray, Nathanael S.
AU - Sabatini, David M.
N1 - Funding Information:
The authors thank Thijn Brummelkamp for reviewing the manuscript and the following for technical assistance: Leslie Brents, Stephen Carr, Jake Jaffe, Xana Frias, Heather Keys, Stephanie Kinkel, Doug McMillin, Jan Reiling, Eric Spooner, Ed Van Veen, and Marcel Van Vugt. We thank members of the Sabatini lab for helpful discussions. This work was supported by grants from the National Institutes of Health (NIH; R01 AI47389 and R01 CA103866) to D.M.S.; awards from the Keck Foundation and LAM Foundation to D.M.S.; a fellowship from the American Diabetes Association to T.R.P.; a fellowship from the Canadian Institutes of Health Research to M.L.; and a fellowship from the American Cancer Society to S.A.K. W.M.K was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. N.S.G. is funded in part by the Dana Farber Cancer Institute High-Tech Research Fund. D.M.S. is an investigator of the Howard Hughes Medical Institute.
PY - 2009/5/29
Y1 - 2009/5/29
N2 - 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.
AB - 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.
KW - HUMDISEASE
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=67349241955&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2009.03.046
DO - 10.1016/j.cell.2009.03.046
M3 - Article
C2 - 19446321
AN - SCOPUS:67349241955
SN - 0092-8674
VL - 137
SP - 873
EP - 886
JO - Cell
JF - Cell
IS - 5
ER -