DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival
Open accessAbstract
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.
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SGK1 is activated by insulin and growth factors via PI3-kinase, PDK1, and mTORC2.
“The kinase is activated by insulin and growth factors via PI3-kinase, the 3-phosphoinositide-dependent kinase PDK1, and the mammalian target of rapamycin mTORC2 (Lang et al. 2006(Lang et al. , 2009;;Peterson et al. 2009).”
From Significance of SGK1 in the regulation of neuronal function (2010) · cites this paper as Peterson et al. 2009
The Introduction (page not provided) says mTORC2 phosphorylates SGK1 in response to growth factors. It does not specify insulin or establish PI3K and PDK1 as steps in SGK1 activation. The Results passage on PI3K and PDK1 concerns Akt, not SGK1. (LLM, conf=0.87)
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- Authors
- Peterson, T. R., Laplante, M., Thoreen, C. C., Sancak, Y., Kang, S. A., Kuehl, W. M., Gray, N. S., & Sabatini, D. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Cancer Institute (US)
- Harvard University (US)
- Corresponding author
- Sabatini, David M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 137
- Issue
- 5
- Pages
- 873-886
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2758791
- OpenAlex
- W2101083009
- Cited by
- 1,202
- References
- 4
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 37 · 2023: 50 · 2022: 66 · 2021: 102 · 2020: 82 · 2019: 61 · 2018: 99 · 2017: 83 · 2016: 83 · 2015: 86 · 2014: 80 · 2013: 84 · 2012: 85
- FWCI
- 29.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1538 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA103866, R01CA129105)
- National Institute of Allergy and Infectious Diseases (R01AI047389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- DEPTOR, mTOR, mTORC1, mTORC2, multiple myeloma, PI3K/Akt signaling, S6K1, SGK1, cell survival, apoptosis, product inhibition
- MeSH terms
- Cell Line, Cell Survival, Humans, Multiple Myeloma, Protein Kinases, Signal Transduction, Cyclins, Phosphatidylinositol 3-Kinases, Cyclin D1, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt, Cyclin D3, TOR Serine-Threonine Kinases
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