Transmembrane inhibitor of RICTOR/mTORC2 in hematopoietic progenitors Journal Article
| Authors: | Lee, D.; Sykes, S. M.; Kalaitzidis, D.; Lane, A. A.; Kfoury, Y.; Raaijmakers, M. H. G. P.; Wang, Y. H.; Armstrong, S. A.; Scadden, D. T. |
| Article Title: | Transmembrane inhibitor of RICTOR/mTORC2 in hematopoietic progenitors |
| 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 AKTS473, PKCa, 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. |
| Keywords: | protein kinase b; controlled study; protein phosphorylation; unclassified drug; nonhuman; cell proliferation; animal cell; mouse; cell survival; protein protein interaction; enzyme activity; cancer mortality; acute lymphoblastic leukemia; animalia; regulatory mechanism; transcription regulation; mammalian target of rapamycin; membrane protein; hematopoietic stem cell; protein kinase c alpha; transcription factor foxo; mammalian target of rapamycin complex 1; mammalian target of rapamycin complex 2; priority journal; article; protein ndrg1; protein rictor |
| Journal Title: | Stem Cell Reports |
| Volume: | 3 |
| Issue: | 5 |
| ISSN: | 2213-6711 |
| Publisher: | Cell Press |
| Date Published: | 2014-11-11 |
| Start Page: | 832 |
| End Page: | 840 |
| Language: | English |
| DOI: | 10.1016/j.stemcr.2014.08.011 |
| PROVIDER: | scopus |
| PMCID: | PMC4235746 |
| PUBMED: | 25418727 |
| DOI/URL: | |
| Notes: | Export Date: 2 March 2015 -- Source: Scopus |
