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Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2016 Mar 04; Vol. 291 (10), pp. 5221-33. Date of Electronic Publication: 2016 Jan 06. - Publication Year :
- 2016
-
Abstract
- 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.<br /> (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Arginine chemistry
Arginine pharmacology
Carbamates chemistry
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation drug effects
HEK293 Cells
Humans
Mechanistic Target of Rapamycin Complex 1
Phosphoproteins metabolism
Phosphorylation
Protein Binding
Protein Biosynthesis
Protein Processing, Post-Translational
Ribosomal Protein S6 Kinases metabolism
Ubiquitins antagonists & inhibitors
Ubiquitins genetics
Arginine analogs & derivatives
Carbamates pharmacology
Enzyme Inhibitors pharmacology
Multiprotein Complexes metabolism
Signal Transduction
TOR Serine-Threonine Kinases metabolism
Ubiquitins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 291
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26740621
- Full Text :
- https://doi.org/10.1074/jbc.M115.691584