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.