Rapamycin‐mediated mTORC 2 inhibition is determined by the relative expression of FK 506‐binding proteins

Abstract

The mechanism by which the drug rapamycin inhibits the mechanistic target of rapamycin (mTOR) is of intense interest because of its likely relevance in cancer biology, aging, and other age-related diseases. While rapamycin acutely and directly inhibits mTORC1, only chronic administration of rapamycin can inhibit mTORC2 in some, but not all, cell lines or tissues. The mechanism leading to cell specificity of mTORC2 inhibition by rapamycin is not understood and is especially important because many of the negative metabolic side effects of rapamycin, reported in mouse studies and human clinical trials, have been attributed recently to mTORC2 inhibition. Here, we identify the expression level of different FK506-binding proteins (FKBPs), primarily FKBP12 and FKBP51, as the key determinants for rapamycin-mediated inhibition of mTORC2. In support, enforced reduction of FKBP12 completely converts a cell line that is sensitive to mTORC2 inhibition to an insensitive cell line, and increased expression can enhance mTORC2 inhibition. Further reduction of FKBP12 in cell lines with already low FKBP12 levels completely blocks mTORC1 inhibition by rapamycin, indicating that relative FKBP12 levels are critical for both mTORC1 and mTORC2 inhibition, but at different levels. In contrast, reduction of FKBP51 renders cells more sensitive to mTORC2 inhibition. Our findings reveal that the expression of FKBP12 and FKBP51 is the rate limiting factor that determines the responsiveness of a cell line or tissue to rapamycin. These findings have implications for treating specific diseases, including neurodegeneration and cancer, as well as targeting aging in general.

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

“…However, Schreiber et al . (2015) have suggested that rapamycin effects on mTORC2 signaling may be difficult to detect, and we cannot rule out the idea that mTORC2 could also play an important role in regulating MGMT and NDRG1 expression in the slow‐aging mice.…”

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

“…We and others have found that chronic treatment with rapamycin inhibits not only mTORC1, but also inhibits mTORC2 in numerous tissues, including liver, muscle, adipose tissue, and heart (Lamming et al ., 2012; Schreiber et al ., 2015). The role of mTORC2 in aging is not yet clear, as mice with decreased expression of Rictor , an essential component of mTORC2, have a male‐specific decrease in lifespan, while mice heterozygous for Akt1 have increased lifespan (Nojima et al ., 2013; Lamming et al ., 2014b).…”

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

“…Consistent with its effects on glucose homeostasis, chronic rapamycin treatment can disrupt mTORC2 signaling in liver, skeletal muscle, and adipose tissues as well as many others (Lamming et al ., 2012; Schreiber et al ., 2015). Interestingly, in the present study, we observe decreased AKT S473 phosphorylation in the skeletal muscle of mice treated daily with rapamycin (Fig.…”

“…S2A). The effect of chronic rapamycin treatment on AKT S473 phosphorylation can be difficult to observe and is time sensitive (Schreiber et al ., 2015), and so we may have only observed this effect in skeletal muscle due to the time point utilized. The impact of chronic rapamycin on AKT S473 phosphorylation is also influenced by diet (Liu et al ., 2014).…”