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 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.
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Lee
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sykes
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Demetrios
authors.initials: D
authors.lastname: Kalaitzidis
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lane
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Youmna
authors.initials: Y
authors.lastname: Kfoury
authors.affiliation: Department of Hematology and Erasmus Stem Cell Institute, Erasmus University Medical Center, 3015GE Rotterdam, the Netherlands.
authors.forename: Marc H G P
authors.initials: MH
authors.lastname: Raaijmakers
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: david_scadden@harvard.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051880:Receptors, Notch / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D026901:Membrane Transport Proteins; D046912:Multiprotein Complexes; D051571:Protein Kinase C-alpha; D051057:Proto-Oncogene Proteins c-akt; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051880:Receptors, Notch; D058570:TOR Serine-Threonine Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C474033:FoxO3 protein, mouse; C525637:rictor protein, mouse