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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/3/C583    most recent 00464.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Miyazaki, M. Articles by Esser, K. A. Search for Related Content PubMed PubMed Citation Articles by Miyazaki, M. Articles by Esser, K. A.

MUSCLE CELL BIOLOGY AND CELL MOTILITY

REDD2 is enriched in skeletal muscle and inhibits mTOR signaling in response to leucine and stretch

Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky

Submitted 8 September 2008 ; accepted in final form 5 January 2009

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.

tuberous sclerosis complex 1; tuberous sclerosis complex 2; 14-3-3 protein; S6 kinase 1; Ras homolog enriched in brain; mammalian target of rapamycin; regulated in development and DNA damage responses 2