Published online before print November 16, 2006, doi: 10.1161/01.RES.0000252830.01581.fd
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Submitted on August 25, 2006
Revised on October 19, 2006
Accepted on November 7, 2006
1-Adrenergic Receptors Activate AKT via a Pyk2/PDK-1 Pathway That Is Tonically Inhibited by Novel Protein Kinase C Isoforms in Cardiomyocytes
Jianfen Guo ;
From the Department of Pharmacology (J.G., H.E., V.R., S.F.S.), College of Physicians and Surgeons, Columbia University, New York; and Department of Anatomy and Cell Biology (A.S.), Temple University, Philadelphia, Pa.
* To whom correspondence should be addressed. E-mail: sfs1{at}columbia.edu.
AKT is a potent antiapoptotic kinase, but its role in the cardioprotective actions of 
1-adrenergic receptors (ARs) remains uncertain, because 1-ARs typically induce little-to-no AKT activation in most cardiomyocyte models. This study identifies a prominent 1-AR-dependent AKT activation pathway that is under tonic inhibitory control by novel protein kinase Cs (nPKCs) in neonatal rat cardiomyocyte cultures. We also implicate Pyk2, Pyk2 complex formation with PDK-1 and paxillin, and increased PDK-1-Y373/376 phosphorylation as the mechanism that links 1-AR activation to increased AKT phosphorylation. nPKCs (which are prominent 1-AR effectors) interfere with this 1-AR-dependent AKT activation by blocking Pyk2/PDK-1/paxillin complex formation and PDK-1-Y373/376 phosphorylation. Additional studies used an adenoviral-mediated overexpression strategy to show that Pyk2 exerts dual controls on antiapoptotic PDK-1/AKT and proapoptotic c-Jun N-terminal kinase (JNK) pathways. Although the high nPKC activity of most cardiomyocyte models favors Pyk2 signaling to JNK (and cardiac apoptosis), the cardioprotective actions of Pyk2 through the PDK-1/AKT pathway are exposed when PKC or JNK activation is prevented. Collectively, these studies identify JNK and AKT as functionally distinct downstream components of the 1-AR/Pyk2 signaling pathway. We also implicate nPKCs as molecular switches that control the balance of signaling via proapoptotic JNK and antiapoptotic PDK-1/AKT pathways, exposing a novel mechanism for nPKC-dependent regulation of cardiac hypertrophy and failure.
Key words: AKT • PDK-1 • Pyk2 • JNK • cardiomyocytes • apoptosis
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