Back to Search
Start Over
Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB
- Source :
- Molecular cell. 22(2)
- Publication Year :
- 2006
-
Abstract
- The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Here we show that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolonged rapamycin treatment reduces the levels of mTORC2 below those needed to maintain Akt/PKB signaling. The proapoptotic and antitumor effects of rapamycin are suppressed in cells expressing an Akt/PKB mutant that is rapamycin resistant. Our work describes an unforeseen mechanism of action for rapamycin that suggests it can be used to inhibit Akt/PKB in certain cell types.
- Subjects :
- Male
Time Factors
Cell Survival
Immunoblotting
Transplantation, Heterologous
Mice, Nude
Apoptosis
mTORC1
Biology
mTORC2
Cell Line
Jurkat Cells
Mice
Cell Line, Tumor
TOR complex
Animals
Humans
Phosphorylation
Protein kinase B
MLST8
Molecular Biology
PI3K/AKT/mTOR pathway
Sirolimus
Antibiotics, Antineoplastic
RPTOR
Cell Biology
Immunohistochemistry
Precipitin Tests
Cell biology
Retroviridae
Cancer research
Trans-Activators
TOR Serine-Threonine Kinases
HT29 Cells
Proto-Oncogene Proteins c-akt
Neoplasm Transplantation
HeLa Cells
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 10972765
- Volume :
- 22
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Molecular cell
- Accession number :
- edsair.doi.dedup.....fcc7ca2dfbef7a26c1a38c95209e50a1