Distinct sensor pathways in the hierarchical control of SNAT2, a putative amino acid transceptor, by amino acid availability.
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.
Hyde
Russell
R
Division of Molecular Physiology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
Cwiklinski
Emma L
EL
MacAulay
Katrina
K
Taylor
Peter M
PM
Hundal
Harinder S
HS
D026924:Amino Acid Transport System A / Q000096:biosynthesis* / Q000235:genetics; D021542:Amino Acids, Neutral / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000235:genetics
D026924:Amino Acid Transport System A; D021542:Amino Acids, Neutral; D029721:Drosophila Proteins; C491146:RasGAP1 protein, Drosophila; C498797:SLC38A2 protein, human; D020703:ras GTPase-Activating Proteins; D048670:MAP Kinase Kinase 4