LAUSR

Description RapaLink1 enables differentiation between functions mediated by the closely related mTORC1 and mTORC2. A tale of two complexes The kinase mTOR is a component of two multiprotein complexes, mTORC1 and mTORC2, which have distinct cellular functions. The compound rapamycin does not completely inhibit the kinase activity of mTORC1 and partially inhibits that of mTORC2 in certain cell types. Yang et al. used the rapamycin derivative RapaLink1 to differentiate between those functions mediated by mTORC1 and mTORC2. Because RapaLink1 had improved specificity for mTORC1 compared to rapamycin, the authors showed that cell proliferation and autophagy were regulated by mTORC1, whereas glycolysis was regulated by both complexes, and that starvation resistance in Drosophila was mediated by TORC1. These results demonstrate the utility of RapaLink1 in characterizing the cellular processes regulated by mTORC1 and mTORC2. Rapamycin extends maximal life span and increases resistance to starvation in many organisms. The beneficial effects of rapamycin are thought to be mediated by its inhibitory effects on the mechanistic target of rapamycin complex 1 (mTORC1), although it only partially inhibits the kinase activity of mTORC1. Other mTOR kinase inhibitors have been developed, such as Torin-1, but these readily cross-react with mTORC2. Here, we report the distinct characteristics of a third-generation mTOR inhibitor called RapaLink1. We found that low doses of RapaLink1 inhibited the phosphorylation of all mTORC1 substrates tested, including those whose phosphorylation is sensitive or resistant to inhibition by rapamycin, without affecting mTORC2 activity even after prolonged treatment. Compared with rapamycin, RapaLink1 showed better efficacy for inhibiting mTORC1 and potently blocked cell proliferation and induced autophagy. Moreover, using RapaLink1, we demonstrated that mTORC1 and mTORC2 exerted differential effects on cell glycolysis and glucose uptake. Last, we found that RapaLink1 and rapamycin had opposing effects on starvation resistance in Drosophila. Consistent with the effects of RapaLink1, genetic blockade of mTORC1 activity made flies more sensitive to starvation, reflecting the complexity of the mTORC1 network that extends beyond effects that can be inhibited by rapamycin. These findings extend our understanding of mTOR biology and provide insights into some of the beneficial effects of rapamycin.