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(Circulation Research. 2006;99:1367.)
© 2006 American Heart Association, Inc.

Cellular Biology

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, Abdelkarim Sabri, Hasnae Elouardighi, Vitalyi Rybin, Susan F. Steinberg

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.

Correspondence to Susan F. Steinberg, MD, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 W 168th St, New York, NY 10032. 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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