title: Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway.
abstract: The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Kyu-Sun
authors.initials: KS
authors.lastname: Lee
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Mitra
authors.forename: Abdullah H
authors.initials: AH
authors.lastname: Feroze
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Cheshier
authors.forename: Bingwei
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D011494:Protein Kinases; D051880:Receptors, Notch; D058570:TOR Serine-Threonine Kinases; D000099202:PTEN-Induced Putative Kinase
keywords: Notch; PINK1; cancer stem cells; mTORC2/AKT signaling; mitochondria; neural stem cells