Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling.

Coffey RT, Shi Y, Long MJ, Marr MT, Hedstrom L
J Biol Chem. 2016 291 (10): 5221-33

PMID: 26740621 · PMCID: PMC4777855 · DOI:10.1074/jbc.M115.691584

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular metabolism, growth, and proliferation. mTORC1 has been implicated in many diseases such as cancer, diabetes, and neurodegeneration, and is a target to prolong lifespan. Here we report a small molecule inhibitor (Cbz-B3A) of mTORC1 signaling. Cbz-B3A inhibits the phosphorylation of eIF4E-binding protein 1 (4EBP1) and blocks 68% of translation. In contrast, rapamycin preferentially inhibits the phosphorylation of p70(S6k) and blocks 35% of translation. Cbz-B3A does not appear to bind directly to mTORC1, but instead binds to ubiquilins 1, 2, and 4. Knockdown of ubiquilin 2, but not ubiquilins 1 and 4, decreases the phosphorylation of 4EBP1, suggesting that ubiquilin 2 activates mTORC1. The knockdown of ubiquilins 2 and 4 decreases the effect of Cbz-B3A on 4EBP1 phosphorylation. Cbz-B3A slows cellular growth of some human leukemia cell lines, but is not cytotoxic. Thus Cbz-B3A exemplifies a novel strategy to inhibit mTORC1 signaling that might be exploited for treating many human diseases. We propose that Cbz-B3A reveals a previously unappreciated regulatory pathway coordinating cytosolic protein quality control and mTORC1 signaling.

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (19)

Adaptor Proteins, Signal Transducing Arginine Carbamates Cell Line, Tumor Cell Proliferation Enzyme Inhibitors HEK293 Cells Humans Mechanistic Target of Rapamycin Complex 1 Multiprotein Complexes Phosphoproteins Phosphorylation Protein Binding Protein Biosynthesis Protein Processing, Post-Translational Ribosomal Protein S6 Kinases Signal Transduction TOR Serine-Threonine Kinases Ubiquitins

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