DEPTOR is an mTOR Inhibitor Whose Frequent Overexpression in Multiple Myeloma Cells Promotes their Survival

By Timothy R. Peterson, M. Laplante, C. Thoreen, Y. Sancak, S. A. Kang, W. Kuehl, Nathanael S. Gray, David M. Sabatini. Cell, 2009

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SUMMARY The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR, also called DEPDC6, 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 new mechanism for activating PI3K/Akt signaling and promoting cell survival.

Subfields: Hematology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2e39c7ca99e1316c580118847978bb383c5a724a

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “In addition to these three core components, mTORC1 also contains the two inhibitory subunits PRAS40 (proline-rich Akt substrate of 40 kDa) (Sancak et al., 2007; Vander Haar et al., 2007; Wang et al., 2007) and DEPTOR (DEP domain containing mTOR interacting protein) (Peterson et al., 2009).”
Targets of curcumin (2011, background): “In addition, protor (protein observed with rictor), DEPTOR, PRR5 (proline-rich protein 5) and heat-shock protein 70 (HSP 70) are other novel components of mTORC2 [125,128-130].”
Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress (2010, background): “…with raptor for binding to mTOR (Jacinto et al., 2004; Sarbassov et al., 2004). mTORC2 shares several proteins with mTORC1, such as mLST8 and Deptor (Jacinto et al., 2004; Peterson et al., 2009; Sarbassov et al., 2004), and, like mTORC1, it also appears to be a multimer (Wullschleger et al., 2005).”
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways (2017, background): “mTOR refers to two distinct complexes: mTORC1 is made up of raptor, GbL/mLST8, and negative regulatory subunits PRAS40 and DEPTOR, whereas mTORC2 contains rictor, mSin1, and Protor, GbL/mLST8 and DEPTOR [285].”
Regulation of mTORC1 by amino acids (2014, positive): “Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.”
mTOR signaling at a glance (2009, background): “…mTORC1 directly phosphorylates PRAS40 and Deptor, which reduces their physical interaction with mTORC1 and further activates mTORC1 signaling (Peterson et al., 2009; Wang et al., 2007). mTORC2 mTORC2 comprises six different proteins, several of which are common to mTORC1 and mTORC2: mTOR;…”
mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. (2011, neutral): “Torin1 was previously described (Liu et al., 2010; Thoreen et al., 2009) and was kindly provided by Nathaniel Gray (Harvard Medical School).”
In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P2 to impact mTORC2 and Akt signaling (2016, background): “Peterson TR, et al. (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.”
mTOR signaling in growth control and disease (2012, background): “They share the catalytic mTOR subunit, and also mammalian lethal with sec-13 protein 8 (mLST8, also known as GbL) (Jacinto et al., 2004; Kim et al., 2003), DEP domain containing mTOR-interacting protein (DEPTOR) (Peterson et al., 2009), and the Tti1/Tel2 complex (Kaizuka et al., 2010).”
The mTOR Signalling Pathway in Human Cancer (2012, background): “DEPTOR is a negative regulator of both mTORC1 and mTORC2 [16].”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “The 5.9 Å cryo-EM structure of mTORC1 (without DEPTOR and PRAS40, PDB ID: 5FLC) from is depicted as a space filling model and colored by subunit.”
mTOR: from growth signal integration to cancer, diabetes and ageing (2010, background): “mTORC1 and mTORC2 share mammalian lethal with SEC13 protein 8 (mLST8; also known as GβL) and the recently identified DEP domain-containing mTOR-interacting protein (DEPTOR), which function as positive and negative regulators, respectivel”