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Dexamethasone-Induced Ras Protein 1 Negatively Regulates Protein Kinase C : Implications for Adenylyl Cyclase 2 Signaling

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana

We identified dexamethasone-induced Ras protein 1 (Dexras1) as a negative regulator of protein kinase C (PKC) , and the consequences of this regulation have been examined for adenylyl cyclase (EC 4.6.1.1 [EC] ) type 2 (AC2) signaling. Dexras1 expression in human embryonic kidney 293 cells completely abolished dopamine D₂ receptor-mediated potentiation of AC2 activity, which is consistent with previous reports of its ability to block receptor-mediated G signaling pathways. In addition, Dexras1 significantly reduced phorbol 12-myristate 13-acetate (PMA)-stimulated AC2 activity but did not alter G_s-mediated cAMP accumulation. Dexras1 seemed to inhibit PMA stimulation of AC2 by interfering with PKC autophosphorylation. This effect was selective for the isoform because Dexras1 did not alter autophosphorylation of PKC or PKC. Dexras1 disruption of PKC autophosphorylation resulted in a significant blockade of PKC kinase activity as measured by [-³²P]ATP incorporation using a PKC-specific substrate. Moreover, Dexras1 and PKC coimmunoprecipitated from whole-cell lysates. Dexras1 did not alter the membrane translocation of PKC; however, the ability of Dexras1 to interfere with PKC autophosphorylation was isoprenylation-dependent as determined using the farnesyltransferase inhibitor methyl {N-[2-phenyl-4-N [2(R)-amino-3-mecaptopropylamino] benzoyl]}-methionate (FTI-277) and a CAAX box-deficient Dexras1 (C277S) mutant. PMA-stimulated AC2 activity was also not affected by Dexras1 C277S. Taken as a whole, these data suggest that Dexras1 functionally interacts with PKC at the cellular membrane through an isoprenylation-dependent mechanism to negatively regulate PKC activity. Moreover our study suggests that Dexras1 acts to modulate the activation of AC2 in an indirect fashion by inhibiting both G- and PKC-stimulated AC2 activity. The current study provides a novel role for Dexras1 in signal transduction.

Received for publication September 20, 2005.

Accepted for publication February 17, 2006.

Address correspondence to: Dr. Val J. Watts, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, RHPH 210, West Lafayette, IN 47907. E-mail: wattsv{at}pharmacy.purdue.edu

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