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      Leucine Induced Dephosphorylation of Sestrin2 Promotes mTORC1 Activation

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          Abstract

          The studies described herein were designed to explore the role of Sestrin2 in mediating the selective action of leucine to activate mTORC1. The results demonstrate that Sestrin2 is a phosphoprotein and that its phosphorylation state is responsive to the availability of leucine, but not other essential amino acids. Moreover, leucine availability-induced alterations in Sestrin2 phosphorylation correlated temporally and dose dependently with the activation state of mTORC1, there being a reciprocal relationship between the degree of phosphorylation of Sestrin2 and the extent of repression of mTORC1. With leucine deprivation, Sestrin2 became more highly phosphorylated and interacted more strongly with proteins of the GATOR2 complex. Notably, in cells lacking the protein kinase ULK1, the activation state of mTORC1 was elevated in leucine-deficient medium, such that the effect of re-addition of the amino acid was blunted. In contrast, overexpression of ULK1 led to hyperphosphorylation of Sestrin2 and enhanced its interaction with GATOR2. Neither rapamycin nor Torin2 had any effect on Sestrin2 phosphorylation, suggesting that leucine deprivation-induced repression of mTORC1 was not responsible for the action of ULK1 on Sestrin2. Mass spectrometry analysis of Sestrin2 revealed three phosphorylation sites that are conserved across mammalian species. Mutation of the three sites to phospho-mimetic amino acids in exogenously expressed Sestrin2 promoted its interaction with GATOR2 and dramatically repressed mTORC1 even in the presence of leucine. Overall, the results support a model in which leucine selectively promotes dephosphorylation of Sestrin2, causing it to dissociate from and thereby activate GATOR2, leading to activation of mTORC1.

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          Author and article information

          Journal
          8904683
          1769
          Cell Signal
          Cell. Signal.
          Cellular signalling
          0898-6568
          1873-3913
          17 May 2016
          21 March 2016
          August 2016
          01 August 2017
          : 28
          : 8
          : 896-906
          Affiliations
          [1 ]The Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, PO Box 850, Hershey, PA 17033
          Author notes
          [* ]Correspondence: Scot R. Kimball, Ph.D., Department of Cellular and Molecular Physiology, H166, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey PA 17033; Telephone: (717) 531-8970; Fax: (717) 531-7667; skimball@ 123456psu.edu
          [2]

          Current address: The Department of Sport and Exercise Science, The University of Central Florida, P.O. Box 161250, Orlando, FL 32816

          [†]

          These authors contributed equally to the work described herein

          Article
          PMC4899281 PMC4899281 4899281 nihpa786872
          10.1016/j.cellsig.2016.03.008
          4899281
          27010498
          61d99d00-4304-4d8a-8f11-7a634fe05106
          History
          Categories
          Article

          Rag GTPases,mechanistic target of rapamycin,amino acids,signaling,ULK1

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