Regulation of nutrient signaling to mammalian target of rapamycin by phospholipase D
Item
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Title
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Regulation of nutrient signaling to mammalian target of rapamycin by phospholipase D
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Identifier
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d_2009_2013:3d75af276ef9:11248
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identifier
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11455
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Creator
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Xu, Limei,
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Contributor
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David A. Foster
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Date
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2012
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Language
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English
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Publisher
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City University of New York.
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Subject
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Molecular biology | mTOR | nutrient | phosphatidic acid | Phospholipase D
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Abstract
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The mammalian target of rapamycin (mTOR) is a key component of a complicated signaling network which transduces nutrient signals and many other stimuli to modulate a wide range of cellular functions, such as cell growth, cell proliferation and cell survival. Phospholipase D (PLD) is an enzyme which catalyzes the hydrolysis of phosphatidylcholine (PC) to form phosphatidic acid (PA). PA has been shown to be a very important lipid second messenger that mediates mitogenic signals upstream of mTOR and both PLD and mTOR have been implicated as cancer cell survival signals. Therefore it is of interest as to whether PLD plays a role in mTOR mediated nutrient signaling. We have found that elevated PLD activity in human cancer cells is dependent on the availability of both amino acids and glucose and that PLD is required for amino acid- and glucose-induced mTOR Complex 1 (mTORC1) activity. Moreover we investigated the possible regulators which are involved in mediating the nutrients signals including amino acids and glucose to PLD and mTORC1. We found that small GTPases RalA and ARF6 which form a complex with PLD to activate its activity are required for both PLD and mTORC1 activation induced by amino acids and glucose. The class III phosphatidylinositol-3-kinase hVps34 emerged as an important modulator for amino acid sensing. In this study, we showed that the depletion of hVps34 or binding partner hVps15 with siRNA dramatically suppressed the PLD activity and further disrupted nutrient sensing to mTORC1, possibly by failing to recruit PLD to endomembrane and stimulate mTORC1 activity in response to nutrients. Taken together, these findings demonstrate that phosphatidic acid generated by PLD is a critical mediator that links nutrient signals to mTORC1, thus implicating the important role of PLD and PA in cancer cell proliferation and survival.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
