Abstract
Central to cellular proliferative, survival, and metabolic responses is the serine/threonine kinase mTOR, which is activated in many human cancers. mTOR is present in distinct complexes that are either modulated by AKT (mTORC1) or are upstream and regulatory of it (mTORC2). Governance of mTORC2 activity is poorly understood. Here, we report a transmembrane molecule in hematopoietic progenitor cells that physically interacts with and inhibits RICTOR, an essential component of mTORC2. Upstream of mTORC2 (UT2) negatively regulates mTORC2 enzymatic activity, reducing AKT(S473), PKCα, and NDRG1 phosphorylation and increasing FOXO transcriptional activity in an mTORC2-dependent manner. Modulating UT2 levels altered animal survival in a T cell acute lymphoid leukemia (T-ALL) model that is known to be mTORC2 sensitive. These studies identify an inhibitory component upstream of mTORC2 in hematopoietic cells that can reduce mortality from NOTCH-induced T-ALL. A transmembrane inhibitor of mTORC2 may provide an attractive target to affect this critical cell regulatory pathway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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HEK293 Cells
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism*
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Humans
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Immunoblotting
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Intracellular Signaling Peptides and Proteins / metabolism
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Mechanistic Target of Rapamycin Complex 2
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism*
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Mice
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Mice, Knockout
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Mice, Transgenic
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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NIH 3T3 Cells
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Phosphorylation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Protein Binding
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Protein Kinase C-alpha / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Rapamycin-Insensitive Companion of mTOR Protein
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Receptors, Notch / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Carrier Proteins
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Cell Cycle Proteins
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Transport Proteins
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Multiprotein Complexes
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N-myc downstream-regulated gene 1 protein
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Rapamycin-Insensitive Companion of mTOR Protein
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Receptors, Notch
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rictor protein, mouse
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Protein Kinase C-alpha