RT Journal Article SR Electronic T1 Dexamethasone-Induced Ras Protein 1 Negatively Regulates Protein Kinase C δ: Implications for Adenylyl Cyclase 2 Signaling JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1763 OP 1771 DO 10.1124/mol.105.019133 VO 69 IS 5 A1 Chau H. Nguyen A1 Val J. Watts YR 2006 UL http://molpharm.aspetjournals.org/content/69/5/1763.abstract AB We identified dexamethasone-induced Ras protein 1 (Dexras1) as a negative regulator of protein kinase C (PKC) δ, and the consequences of this regulation have been examined for adenylyl cyclase (EC 4.6.1.1) 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 Gβγ signaling pathways. In addition, Dexras1 significantly reduced phorbol 12-myristate 13-acetate (PMA)-stimulated AC2 activity but did not alter Gαs-mediated cAMP accumulation. Dexras1 seemed to inhibit PMA stimulation of AC2 by interfering with PKCδ autophosphorylation. This effect was selective for the δ isoform because Dexras1 did not alter autophosphorylation of PKCα or PKCϵ. Dexras1 disruption of PKCδ autophosphorylation resulted in a significant blockade of PKC kinase activity as measured by [γ-32P]ATP incorporation using a PKC-specific substrate. Moreover, Dexras1 and PKCδ coimmunoprecipitated from whole-cell lysates. Dexras1 did not alter the membrane translocation of PKCδ; however, the ability of Dexras1 to interfere with PKCδ 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 PKCδ at the cellular membrane through an isoprenylation-dependent mechanism to negatively regulate PKCδ activity. Moreover our study suggests that Dexras1 acts to modulate the activation of AC2 in an indirect fashion by inhibiting both Gβγ- and PKC-stimulated AC2 activity. The current study provides a novel role for Dexras1 in signal transduction.