Transmembrane Inhibitor of RICTOR/mTORC2 in Hematopoietic Progenitors

• Published in: Stem cell reports Vol. 3; no. 5; pp. 832 - 840
• Main Authors: Lee, Dongjun, Sykes, Stephen M., Kalaitzidis, Demetrios, Lane, Andrew A., Kfoury, Youmna, Raaijmakers, Marc H.G.P., Wang, Ying-Hua, Armstrong, Scott A., Scadden, David T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.11.2014; Elsevier
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Cycle Proteins - metabolism; Cells, Cultured; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; HEK293 Cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Immunoblotting; Intracellular Signaling Peptides and Proteins - metabolism; Mechanistic Target of Rapamycin Complex 2; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; NIH 3T3 Cells; Phosphorylation; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Protein Binding; Protein Kinase C-alpha - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin-Insensitive Companion of mTOR Protein; Receptors, Notch - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2014.08.011

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 AKTS473, 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. [Display omitted] •UT2 is a transmembrane inhibitor of mTORC2 in hematopoietic progenitors•UT2 directly binds RICTOR, limiting the kinase activity of mTORC2 on pAKTS473•UT2 modulates the outcome of an mTORC2-dependent hematopoietic cancer In this article, Scadden and colleagues show that an undefined transmembrane molecule upstream of mTORC2 (UT2) negatively regulates AKT signaling via modulation of mTORC2. Their work points to the value of models that can be used to examine niche contributions to oncogenesis and reveals a previously unrecognized transmembrane modulator of a critical pathway with therapeutic implications for cancers such as T-ALL.