The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an essential role in cell growth control. mTOR stimulates cell growth by phosphorylating p70 ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1 (4EBP1). The mTOR pathway is regulated by a wide variety of cellular signals, including mitogenic growth factors, nutrients, cellular energy levels, and stress conditions. Recent studies have proposed several mechanisms to explain how mTOR is regulated by growth factors and cellular energy levels. However, little is known as to how mTOR is regulated by stress conditions. We observed that two stress-induced proteins, RTP801/Redd1 and RTP801L/Redd2, potently inhibit signaling through mTOR. Our data support that RTP801 and RTP801L work downstream of AKT and upstream of TSC2 to inhibit mTOR functions. These results add a new dimension to mTOR pathway regulation and provide a possible molecular mechanism of how cellular stress conditions may regulate mTOR function.
Corradetti
Michael N
MN
Life Sciences Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
Inoki
Ken
K
Guan
Kun-Liang
KL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D047468:Immunoprecipitation; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; C469991:DDIT4 protein, human; C498040:DDIT4L protein, human; D004268:DNA-Binding Proteins; C450979:Ddit4l protein, mouse; D005938:Glucocorticoids; D011506:Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases