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J. Biol. Chem., Vol. 279, Issue 35, 36490-36496, August 27, 2004

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Inhibition of Mammalian Target of Rapamycin Activates Apoptosis Signal-regulating Kinase 1 Signaling by Suppressing Protein Phosphatase 5 Activity^*

Shile Huang¶, Lili Shu, John Easton, Franklin C. Harwood, Glen S. Germain, Hidenori Ichijo||, and Peter J. Houghton

From the Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794 and the ^||Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Under serum-free conditions, rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), induces a cellular stress response characterized by rapid and sustained activation of the apoptosis signal-regulating kinase 1 (ASK1) signaling pathway and selective apoptosis of cells lacking functional p53. Here we have investigated how mTOR regulates ASK1 signaling using p53-mutant rhabdomyosarcoma cells. In Rh30 cells, ASK1 was found to physically interact with protein phosphatase 5 (PP5), previously identified as a negative regulator of ASK1. Rapamycin did not affect either protein level of PP5 or association of PP5 with ASK1. Instead, rapamycin caused rapid dissociation of the PP2A-B'' regulatory subunit (PR72) from the PP5-ASK1 complex, which was associated with reduced phosphatase activity of PP5. This effect was dependent on expression of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Down-regulation of PP5 activity by rapamycin coordinately activated ASK1, leading to elevated phosphorylation of c-Jun. Amino acid deprivation, which like rapamycin inhibits mTOR signaling, also inhibited PP5 activity, caused rapid dissociation of PR72, and activated ASK1 signaling. Overexpression of PP5, but not the PP2A catalytic subunit, blocked rapamycin-induced phosphorylation of c-Jun, and protected cells from rapamycin-induced apoptosis. The results suggest that PP5 is downstream of mTOR, and positively regulated by the mTOR pathway. The findings suggest that in the absence of serum factors, mTOR signaling suppresses apoptosis through positive regulation of PP5 activity and suppression of cellular stress.

Received for publication, February 3, 2004 , and in revised form, June 18, 2004.

^* This work was supported in part by United States Public Health Service awards CA77776 (to P. J. H.), CA96696 (to P. J. H.), CA23099 (to P. J. H.), and CA28765 (Cancer Center Support Grant) (to P. J. H.) from the NCI, National Institutes of Health, by a grant from WyethAyerst Company (to P. J. H.), by a grant-in-aid award (to S. H.), and a start-up fund (to S. H.) jointly from Louisiana State University Health Sciences Center in Shreveport and Feist-Weiller Cancer Center in Shreveport, LA, and American, Lebanese, Syrian-associated Charities (ALSAC) in Memphis, TN. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center,1501 Kings Highway, Shreveport, LA 71130-3932.

^¶ To whom correspondence should be addressed: Dept. of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 Lauderdale, Memphis, TN 38105-2794. Tel.: 901-495-3440; Fax: 901-495-4290; E-mail: peter.houghton{at}stjude.org.

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