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.
Keywords:
Notch; PINK1; cancer stem cells; mTORC2/AKT signaling; mitochondria; neural stem cells.
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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Brain Neoplasms / physiopathology
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Cell Line, Tumor
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Cell Proliferation
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism
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Gene Expression Regulation
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Humans
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Mechanistic Target of Rapamycin Complex 2
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Microscopy, Electron, Transmission
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Mitochondria / enzymology
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Mitochondria / metabolism*
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Mitochondria / ultrastructure
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Mutation
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Neoplastic Stem Cells / metabolism*
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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RNA Interference
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Receptors, Notch / metabolism*
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Signal Transduction*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Multiprotein Complexes
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Receptors, Notch
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Protein Kinases
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Mechanistic Target of Rapamycin Complex 2
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PTEN-induced putative kinase
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TOR Serine-Threonine Kinases