A-Kinase Anchoring Protein Lbc Coordinates a p38 Activating Signaling Complex Controlling Compensatory Cardiac Hypertrophy.

In response to stress, the heart undergoes a remodeling process associated with cardiac hypertrophy that eventually leads to heart failure. A-kinase anchoring proteins (AKAPs) have been shown to coordinate numerous prohypertrophic signaling pathways in cultured cardiomyocytes. However, it remains to be established whether AKAP-based signaling complexes control cardiac hypertrophy and remodeling in vivo. In the current study, we show that AKAP-Lbc assembles a signaling complex composed of the kinases PKN, MLTK, MKK3, and p38α that mediates the activation of p38 in cardiomyocytes in response to stress signals. To address the role of this complex in cardiac remodeling, we generated transgenic mice displaying cardiomyocyte-specific overexpression of a molecular inhibitor of the interaction between AKAP-Lbc and the p38-activating module. Our results indicate that disruption of the AKAP-Lbc/p38 signaling complex inhibits compensatory cardiomyocyte hypertrophy in response to aortic banding-induced pressure overload and promotes early cardiac dysfunction associated with increased myocardial apoptosis, stress gene activation, and ventricular dilation. Attenuation of hypertrophy results from a reduced protein synthesis capacity, as indicated by decreased phosphorylation of 4E-binding protein 1 and ribosomal protein S6. These results indicate that AKAP-Lbc enhances p38-mediated hypertrophic signaling in the heart in response to abrupt increases in the afterload

The A-kinase-anchoring protein AKAP-Lbc facilitates cardioprotective PKA phosphorylation of Hsp20 on Ser16

Hsp20 (heat-shock protein of 20 kDa; HspB6) is a cardioprotective agent which combats a number of pathophysiological processes in the heart, including hypertrophy, apoptosis and ischaemia/reperfusion injury. The cardioprotective actions of Hsp20 require its phosphorylation by PKA (cAMP-dependent protein kinase) on Ser(16). Although the extracellular stimuli that promote cAMP-responsive phosphorylation of Hsp20 are well known, less is understood about the molecular processes that regulate this modification. AKAPs (A-kinase-anchoring proteins) physically compartmentalize PKA to specific locations within a cell to both direct PKA phosphorylation toward selected substrates and to orchestrate downstream signalling events. In the present study we used PKA anchoring disruptor peptides to verify that an AKAP underpins the cardioprotective phosphorylation of Hsp20. Biochemical and immunofluorescence techniques identify the cytosolic protein AKAP-Lbc (AKAP13) as the anchoring protein responsible for directing PKA phosphorylation of Hsp20 on Ser(16). Gene silencing and rescue experiments establish that AKAP-Lbc-mediated PKA phosphorylation of Hsp20 is crucial to the anti-apoptotic effects of the Hsp. Thus AKAP-Lbc may serve an ancillary cardioprotective role by favouring the association of PKA with Hsp20

AKAPs: The architectural underpinnings of local cAMP signaling

The cAMP-dependent protein kinase A (PKA) is targeted to specific compartments in the cardiac myocyte by A-kinase anchoring proteins (AKAPs), a diverse set of scaffold proteins that have been implicated in the regulation of excitation-contraction coupling and cardiac remodeling. AKAPs bind not only PKA, but also a large variety of structural and signaling molecules. In this review, we discuss the basic concepts underlying compartmentation of cAMP and PKA signaling, as well as a few of the individual AKAPs that have been shown to be functionally relevant in the heart