Distinct sensor pathways in the hierarchical control of SNAT2, a putative amino acid transceptor, by amino acid availability

Russell Hyde, Emma L. Cwiklinski, Katrina MacAulay, Peter M. Taylor, Harinder S. Hundal

    Research output: Contribution to journalArticle

    80 Citations (Scopus)

    Abstract

    Mammalian nutrient sensors are novel targets for therapeutic intervention in disease states such as insulin resistance and muscle wasting; however, the proteins responsible for this important task are largely uncharacterized. Toaddress this issue we have dissected an amino acid (AA) sensor/effector regulon that controls the expression of the System A amino acid transporter-SNAT2-in mammalian cells, a paradigm nutrient-responsive process, and found evidence for the convergence of at least two sensor/effector pathways. During AA withdrawal, JNK is activated and induces the expression of SNAT2 in L6 myotubes by stimulating an intronic nutrient-sensitive domain. A sensor for large neutral AA (e.g. Tyr, Gln) inhibits JNK activation and SNAT2 up-regulation. Additionally, shRNA and transporter chimeras demonstrate that SNAT2 provides a repressive signal for gene transcription during AA sufficiency, thus echoing AA sensing by transceptor (transporter-receptor) orthologues in yeast (Gap1/Ssy1) and Drosophila (PATH). Furthermore, the SNAT2 protein is stabilized during AA withdrawal.

    Original languageEnglish
    Pages (from-to)19788-19798
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume282
    Issue number27
    DOIs
    Publication statusPublished - 6 Jul 2007

    Cite this

    Hyde, Russell ; Cwiklinski, Emma L. ; MacAulay, Katrina ; Taylor, Peter M. ; Hundal, Harinder S. / Distinct sensor pathways in the hierarchical control of SNAT2, a putative amino acid transceptor, by amino acid availability. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 27. pp. 19788-19798.
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    abstract = "Mammalian nutrient sensors are novel targets for therapeutic intervention in disease states such as insulin resistance and muscle wasting; however, the proteins responsible for this important task are largely uncharacterized. Toaddress this issue we have dissected an amino acid (AA) sensor/effector regulon that controls the expression of the System A amino acid transporter-SNAT2-in mammalian cells, a paradigm nutrient-responsive process, and found evidence for the convergence of at least two sensor/effector pathways. During AA withdrawal, JNK is activated and induces the expression of SNAT2 in L6 myotubes by stimulating an intronic nutrient-sensitive domain. A sensor for large neutral AA (e.g. Tyr, Gln) inhibits JNK activation and SNAT2 up-regulation. Additionally, shRNA and transporter chimeras demonstrate that SNAT2 provides a repressive signal for gene transcription during AA sufficiency, thus echoing AA sensing by transceptor (transporter-receptor) orthologues in yeast (Gap1/Ssy1) and Drosophila (PATH). Furthermore, the SNAT2 protein is stabilized during AA withdrawal.",
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    Distinct sensor pathways in the hierarchical control of SNAT2, a putative amino acid transceptor, by amino acid availability. / Hyde, Russell; Cwiklinski, Emma L.; MacAulay, Katrina; Taylor, Peter M.; Hundal, Harinder S.

    In: Journal of Biological Chemistry, Vol. 282, No. 27, 06.07.2007, p. 19788-19798.

    Research output: Contribution to journalArticle

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