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J. Biol. Chem., Vol. 283, Issue 34, 23129-23138, August 22, 2008

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A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation^*

From the Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Rap1b has been implicated in the transduction of the cAMP mitogenic signal. It is phosphorylated and activated by cAMP, and its expression in models where cAMP is mitogenic leads to proliferation and tumorigenesis. Akt is a likely downstream effector of cAMP-Rap1 action. cAMP elevation induced a rapid and transient Akt inhibition that required activated and phosphorylated Rap1b. However, the mechanism(s) by which cAMP-Rap regulates Akt remains unclear. Here we show that (i) upstream regulators, PIK and PDK1, are not the target(s) of the cAMP inhibitory action; (ii) constitutively active Akt and calyculin A-stimulated Akt are resistant to cAMP inhibition, suggesting the action of a phosphatase; (iii) cAMP increases the rate of Akt dephosphorylation, directly implicating an Akt-phosphatase; (iv) Epac- and protein kinase A (PKA)-specific analogs synergistically inhibit Akt, indicating the involvement of both cAMP-dependent effector pathways; (v) H89 and dominant negative Epac 279E block cAMP-inhibitory action; (vi) Epac associates in a complex with Akt and PP2A, and the associated-phosphatase activity is positively modulated by cAMP in a PKA- and Rap1-dependent manner; (vii) like its action on Akt inhibition, PKA- and Epac-specific analogs synergistically activate Epac-associated PP2A; and (viii) dominant negative PP2A blocks cAMP-inhibitory action. Thus, we uncovered a novel cAMP-Epac/PKA-Rap1b-PP2A signaling module involved in Akt regulation that may represent a physiological event in the process of cAMP stimulation of thyroid mitogenesis.

Received for publication, January 18, 2008 , and in revised form, May 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Public Health Service, NCI, Grant CA071649. 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 Present address: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China.

² To whom correspondence should be addressed: Dept. of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, 200 Lothrop St., W1346 BSTWR, Pittsburgh, PA 15261. Tel.: 412-648-9751; Fax: 412-648-1945; E-mail: altschul{at}pitt.edu.

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