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.
Highlights
Mammalian target of rapamycin3 is an evolutionarily conserved Ser/Thr kinase that serves as a master regulator of many cellular functions, including mRNA translation, autophagy, and cellular proliferation. mTOR integrates growth signals and the availability of amino acids
MTOR is found in two main complexes, mTOR complex 1 and mTOR complex 2, which phosphorylate different downstream targets
4EBP1 appears to be a substrate for several protein kinases, the majority of 4EBP1 phosphorylation occurs via the action of mTOR complex 1 (mTORC1)
Summary
Mammalian target of rapamycin (mTOR)3 is an evolutionarily conserved Ser/Thr kinase that serves as a master regulator of many cellular functions, including mRNA translation, autophagy, and cellular proliferation. mTOR integrates growth signals and the availability of amino acids. Cbz-B3A inhibits the phosphorylation of eIF4E-binding protein 1 (4EBP1) and blocks 68% of translation. The knockdown of ubiquilins 2 and 4 decreases the effect of Cbz-B3A on 4EBP1 phosphorylation. We show that Cbz-B3A blocks translation by inhibiting the mTORC1 pathway in a process that is dependent on the presence of ubiquilins 2 and 4.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call