Human Molecular Genetics Advance Access originally published online on June 8, 2009
Human Molecular Genetics 2009 18(17):3298-3310; doi:10.1093/hmg/ddp271
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Functional interaction of mammalian target of rapamycin complexes in regulating mammalian cell size and cell cycle
Medical Genetics, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
* To whom correspondence should be addressed. Tel: +43 1 40400 7847; Fax: +43 1 40400 7848; Email: markus.hengstschlaeger{at}meduniwien.ac.at
Received May 14, 2009; Revised May 14, 2009; Accepted June 4, 2009
Dysregulation of the mammalian target of rapamycin (mTOR) kinase pathway is centrally involved in a wide variety of cancers and human genetic diseases. In mammalian cells, mTOR is part of two different kinase complexes: mTORC1 composed of mTOR, raptor and mLST8, and mTORC2 containing mTOR, rictor, sin1 and mLST8. Whereas, mTORC1 is known to be a pivotal regulator of cell size and cell cycle control, the question whether the recently discovered mTORC2 complex is involved in these processes remains elusive. We report here that the mTORC1-mediated consequences on cell cycle and cell size are separable and do not involve effects on mTORC2 activity. However, we show that mTORC2 itself is a potent regulator of mammalian cell size and cell cycle via a mechanism involving the Akt/TSC2/Rheb cascade. Our data are of relevance for the understanding of the molecular development of the many human diseases caused by deregulation of upstream and downstream effectors of mTOR.