Open AccessRapamycin‐mediated mTORC 2 inhibition is determined by the relative expression of FK 506‐binding proteins
Author(s) -
Schreiber Katherine H.,
Ortiz Denise,
Academia Emmeline C.,
Anies Arieanna C.,
Liao ChenYu,
Kennedy Brian K.
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12313
Subject(s) - mtorc2 , mtorc1 , pi3k/akt/mtor pathway , mechanistic target of rapamycin , biology , fkbp , microbiology and biotechnology , growth inhibition , cancer research , cell culture , cell growth , pharmacology , signal transduction , biochemistry , genetics
Summary 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 mTORC 1, only chronic administration of rapamycin can inhibit mTORC 2 in some, but not all, cell lines or tissues. The mechanism leading to cell specificity of mTORC 2 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 mTORC 2 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 mTORC 2. In support, enforced reduction of FKBP12 completely converts a cell line that is sensitive to mTORC 2 inhibition to an insensitive cell line, and increased expression can enhance mTORC 2 inhibition. Further reduction of FKBP12 in cell lines with already low FKBP12 levels completely blocks mTORC 1 inhibition by rapamycin, indicating that relative FKBP12 levels are critical for both mTORC 1 and mTORC 2 inhibition, but at different levels. In contrast, reduction of FKBP51 renders cells more sensitive to mTORC 2 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.