DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival

Abstract

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.

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…DEPTOR is an mTOR inhibitor that is overexpressed in multiple myeloma cells and is essential for their survival. 74 The mTOR/Raptor/mLST8/DEPTOR complex (mTORC1) is sensitive to rapamycin and, importantly, inhibits Akt via a negative feedback loop, which involves, at least in part, p70 S6K . 75 This is due to the negative effects that p70 S6K has on insulin receptor substrate-1 (ref.…”

“…Assuming that equilibrium exists between these two complexes, when the mTORC1 complex is formed, it could antagonize the formation of the mTORC2 complex and reduce Akt activity. [73][74][75] Thus, at least in principle, inhibition of the mTORC1 complex could result in Akt hyperactivation. This is one problem associated with therapeutic approaches using rapamycin that blocks some actions of mTORC1, but not all.…”

Rictor is a novel target of p70 S6 kinase-1

“…They share the same catalytic subunit, the highly conserved Ser/Thr kinase mTOR (mammalian target of rapamycin, also known as mechanistic target of rapamycin), which is a major regulator of cell growth, proliferation and survival (Guertin and Sabatini, 2007). mTORC1 consists of mTOR, Raptor (Regulatoryassociated protein of mTOR), mLST8/GbL, PRAS40 (proline-rich Akt substrate of 40KD) and DEPTOR (Hara et al, 2002;Kim et al, 2002Kim et al, , 2003Loewith et al, 2002;Sancak et al, 2007;Vander Haar et al, 2007;Peterson et al, 2009). This complex plays a major role in the regulation of cell growth in response to amino acids, energy sufficiency and growth factors by regulating several cellular processes, including translation, transcription, ribosome biogenesis, nutrients transport and autophagy.…”

“…The ribosomal S6 kinases (S6Ks) and the eukaryotic initiation factor 4E-binding protein-1, both of which regulate protein synthesis, are the bestcharacterized mTORC1 substrates and play a critical role in the control of cell growth by mTORC1 (Inoki et al, 2005;Wullschleger et al, 2006;Ma and Blenis, 2009). The second complex, mTORC2, also contains mTOR, mLST8/GbL and DEPTOR associated with Rictor (the rapamycin-insensitive companion of mTOR), Sin1 (stress-activated, protein kinase-interacting protein-1) and Protor (protein associated with Rictor) (Jacinto et al, 2004(Jacinto et al, , 2006Sarbassov et al, 2004;Frias et al, 2006;Yang et al, 2006;Pearce et al, 2007;Peterson et al, 2009). mTOR assembled into mTORC2 modulates cell proliferation and survival in response to growth factors by promoting the phosphorylation and activation of Akt/PKB, PKC (protein kinase-C) and SGK1 (serum-glucocorticoid-induced protein kinase-1) (Sarbassov et al, 2004(Sarbassov et al, , 2005Guertin et al, 2006;Facchinetti et al, 2008;Garcia-Martinez and Alessi, 2008;Ikenoue et al, 2008).…”

AATF: A new actor in the complex world of mTOR

“…9 Consistent with the control of Deptor expression by AATF, analysis of 559 MMs from a specific dataset revealed a linear correlation between AATF and Deptor mRNA expression. These data were further confirmed by analysis of AATF and Deptor expression in 120 human primary MM samples.…”