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J. Biol. Chem., Vol. 281, Issue 22, 15050-15057, June 2, 2006

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PDE7A1, a cAMP-specific Phosphodiesterase, Inhibits cAMP-dependent Protein Kinase by a Direct Interaction with C^*

Ping Han, Pushpalatha Sonati, Charles Rubin, and Tamar Michaeli¹

From the Departments of Developmental and Molecular Biology and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

The N-terminal regulatory region of the high affinity cAMP-specific phosphodiesterase, PDE7A1, contains two copies of the cAMP-dependent kinase (PKA) pseudosubstrate site RRGAI. In TC3 insulinoma cells, PDE7A1 co-localizes with PKA II in the Golgi-centrosome region. The roles PDE7A1 and its regulatory region play in cAMP signaling were examined by studying interactions with PKA subunits. PDE7A1 associates with the dissociated C subunit of PKA (C), but does not bind tetrameric PKA holoenzyme. High affinity binding of C by PDE7A1 inhibits kinase activity in vitro (IC₅₀ = 0.5 nM). The domain containing PKA pseudosubstrate sites at the N terminus of PDE7A1 mediates complex formation with C. The PDE7A1 N-terminal repeat region inhibits C activity in CHO-K1 cells and also suppresses C dependent, cAMP-independent, physiological responses in yeast. Thus, PDE7A1 possesses a non-catalytic activity that can contribute to the termination of cAMP signals via direct inhibition of C. This study identifies a novel inhibitor of PKA and a non-catalytic affect of a cyclic nucleotide phosphodiesterase.

Received for publication, February 10, 2006

^* This work was supported in part by the Diabetes Research and Training Center Grant DK20541 (to T. M.), by an American Diabetes Association Career Development Award (to T. M.), and by National Institutes of Health Grants DK-58871 (to T. M.) and GM-22792 (to C. R.). 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. Tel.: 718-430-2138; Fax: 253-276-0348; E-mail: michaeli{at}aecom.yu.edu.

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