Abstract
Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation
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Cell Line
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Gene Expression Regulation
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Leucine / antagonists & inhibitors
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Leucine / pharmacology*
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Lysosomes / drug effects
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Lysosomes / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Monomeric GTP-Binding Proteins / genetics
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Monomeric GTP-Binding Proteins / metabolism
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Multiprotein Complexes / agonists
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / genetics*
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Multiprotein Complexes / metabolism
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Muscle Fibers, Skeletal / cytology
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Muscle Fibers, Skeletal / drug effects*
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Muscle Fibers, Skeletal / metabolism
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Myoblasts / cytology
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Myoblasts / drug effects
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Myoblasts / metabolism
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Neuropeptides / genetics
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Neuropeptides / metabolism
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Protein Binding
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Raptors / genetics
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Raptors / metabolism
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Ras Homolog Enriched in Brain Protein
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics*
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TOR Serine-Threonine Kinases / metabolism
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Triterpenes / pharmacology*
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Ursolic Acid
Substances
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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Neuropeptides
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Ras Homolog Enriched in Brain Protein
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Rheb protein, mouse
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Triterpenes
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Tsc1 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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deptor protein, mouse
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mTOR protein, mouse
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Monomeric GTP-Binding Proteins
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RagB protein, mouse
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Leucine