REDD2 is enriched in skeletal muscle and inhibits mTOR signaling in response to leucine and stretch.
The protein kinase mammalian target of rapamycin (mTOR) is well established as a key regulator of skeletal muscle size. In this study, we determined that the stress responsive gene REDD2 (regulated in development and DNA damage responses 2) is a negative regulator of mTOR signaling and is expressed predominantly in skeletal muscle. Overexpression of REDD2 in muscle cells significantly inhibited basal mTOR signaling and diminished the response of mTOR to leucine addition or mechanical stretch. The inhibitory function of REDD2 on mTOR signaling seems to be mediated downstream or independent of Akt signaling and upstream of Rheb (Ras homolog enriched in brain). Knock down of tuberous sclerosis complex 2 (TSC2) using small interfering (si)RNA potently activated mTOR signaling and was sufficient to rescue REDD2 inhibition of mTOR activity, suggesting that REDD2 functions by modulating TSC2 function. Immunoprecipitation assays demonstrated that REDD2 does not directly interact with either TSC1 or TSC2. However, we found that REDD2 forms a complex with 14-3-3 protein and that increasing expression of REDD2 acts to competitively dissociate TSC2 from 14-3-3 and inhibits mTOR signaling. These findings demonstrate that REDD2 is a skeletal muscle specific inhibitory modulator of mTOR signaling and identify TSC2 and 14-3-3 as key molecular links between REDD2 and mTOR function.
Miyazaki
Mitsunori
M
Dept. of Physiology, College of Medicine, Univ. of Kentucky, 800 Rose St., UKMC MS508, Lexington, KY 40536, USA.
Esser
Karyn A
KA
D048948:14-3-3 Proteins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins; D006801:Humans; D007930:Leucine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D013314:Stress, Mechanical; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D014162:Transfection; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C498040:DDIT4L protein, human; D004268:DNA-Binding Proteins; C450979:Ddit4l protein, mouse; D009479:Neuropeptides; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D007930:Leucine