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J. Biol. Chem., Vol. 283, Issue 5, 2575-2585, February 1, 2008

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mTORC1 Signaling Can Regulate Growth Factor Activation of p44/42 Mitogen-activated Protein Kinases through Protein Phosphatase 2A^*

From the Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

The mTORC1 complex (mammalian target of rapamycin (mTOR)-raptor) is modulated by mitogen-activated protein (p44/42 MAP) kinases (p44/42) through phosphorylation and inactivation of the tuberous sclerosis complex. However, a role for mTORC1 signaling in modulating activation of p44/42 has not been reported. We show that in two cancer cell lines regulation of the p44/42 MAPKs is mTORC1-dependent. In Rh1 cells rapamycin inhibited insulin-like growth factor-I (IGF-I)-stimulated phosphorylation of Thr²⁰² but not Tyr²⁰⁴ and suppressed activation of p44/42 kinase activity. Down-regulation of raptor, which inhibits mTORC1 signaling, had a similar effect to rapamycin in blocking IGF-I-stimulated Tyr²⁰⁴ phosphorylation. Rapamycin did not block maximal phosphorylation of Tyr²⁰⁴ but retarded the rate of dephosphorylation of Tyr²⁰⁴ following IGF-I stimulation. IGF-I stimulation of MEK1 phosphorylation (Ser^217/221) was not inhibited by rapamycin. Higher concentrations of rapamycin (100 ng/ml) were required to inhibit epidermal growth factor (EGF)-induced phosphorylation of p44/42 (Thr²⁰²). Rapamycin-induced inhibition of p44/42 (Thr²⁰²) phosphorylation by IGF-I was reversed by low concentrations of okadaic acid, suggesting involvement of protein phosphatase 2A (PP2A). Both IGF-I and EGF caused dissociation of PP2A catalytic subunit (PP2Ac) from p42. Whereas low concentrations of rapamycin (1 ng/ml) inhibited dissociation of PP2Ac after IGF-I stimulation, it required higher concentrations (100 ng/ml) to block EGF-induced dissociation, consistent with the ability for rapamycin to attenuate growth factor-induced activation of p44/42. The effect of rapamycin on IGF-I or insulin activation of p44/42 was recapitulated by amino acid deprivation. Rapamycin effects altering the kinetics of p44/42 phosphorylation were completely abrogated in Rh1mTORrr cells that express a rapamycin-resistant mTOR, whereas the effects of amino acid deprivation were similar in Rh1 and Rh1mTORrr cells. These results indicate complex regulation of p44/42 by phosphatases downstream of mTORC1. This suggests a model in which mTORC1 modulates the phosphorylation of Thr²⁰² on p44/42 MAPKs through direct or indirect regulation of PP2Ac.

Received for publication, July 26, 2007 , and in revised form, November 28, 2007.

^* This work was supported by USPHS Grants CA77776, CA23099, and CA21675 (Cancer Center Support Grant), and by American, Lebanese, Syrian Associated Charities. 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.

¹ To whom correspondence should be addressed: Dept. of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105-2794. Tel.: 901-495-3440; Fax: 901-495-4290; E-mail: peter.houghton{at}stjude.org.

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