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J. Biol. Chem., Vol. 282, Issue 27, 19788-19798, July 6, 2007

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Distinct Sensor Pathways in the Hierarchical Control of SNAT2, a Putative Amino Acid Transceptor, by Amino Acid Availability^*

From the Division of Molecular Physiology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom

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. To address 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.

Received for publication, December 15, 2006 , and in revised form, April 6, 2007.

^* This work was funded by the UK Biotechnology & Biological Sciences Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5 and Table S1.

¹ To whom correspondence should be addressed. Tel.: 44-1382-384969; Fax: 44-1382-385507; E-mail: h.s.hundal{at}dundee.ac.uk.

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