Coordination of Three Signaling Enzymes by AKAP79, a Mammalian Scaffold Protein

Vollum Institute, Oregon Health Sciences University, Portland, 97201, USA.
Science (Impact Factor: 33.61). 04/1996; 271(5255):1589-92. DOI: 10.1126/science.271.5255.1589
Source: PubMed


Multivalent binding proteins, such as the yeast scaffold protein Sterile-5, coordinate the location of kinases by serving as platforms for the assembly of signaling units. Similarly, in mammalian cells the cyclic adenosine 3',5'-monophosphate-dependent protein kinase (PKA) and phosphatase 2B [calcineurin (CaN)] are complexed by an A kinase anchoring protein, AKAP79. Deletion analysis and binding studies demonstrate that a third enzyme, protein kinase C (PKC), binds AKAP79 at a site distinct from those bound by PKA or CaN. The subcellular distributions of PKC and AKAP79 were similar in neurons. Thus, AKAP79 appears to function as a scaffold protein for three multifunctional enzymes.

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    • "For example mAKAP confers bi-directional control of ryanodine receptor phosphorylation during excitation–contraction (EC) coupling; AKAP18γ manages calcium reuptake through the SERCA2 pump and AKAP-Lbc directs the nuclear export of class 2 histone deacetylases in response to hypertrophic signals [16,20,565758596061626364. A common feature of these anchored signaling complexes is the ability to synchronize calcium and cAMP signaling pathways [15]. The AKAP79/150 family of anchoring proteins embodies this property through their capacity to direct protein kinase A (PKA), protein kinase C (PKC) and calcineurin toward selected substrates [11, 31]. In mouse ventricular myocytes it has been shown that AKAP150 targets its cohort of calcium and cAMP responsive enzymes to Ca V 1.2 channels [44]. "
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    ABSTRACT: The Ca(2+)-responsive phosphatase calcineurin/protein phosphatase 2B dephosphorylates the transcription factor NFATc3. In the myocardium activation of NFATc3 down-regulates the expression of voltage-gated K(+) (Kv) channels after myocardial infarction (MI). This prolongs action potential duration and increases the probability of arrhythmias. Although recent studies infer that calcineurin is activated by local and transient Ca(2+) signals the molecular mechanism that underlies the process is unclear in ventricular myocytes. Here we test the hypothesis that sequestering of calcineurin to the sarcolemma of ventricular myocytes by the anchoring protein AKAP150 is required for acute activation of NFATc3 and the concomitant down-regulation of Kv channels following MI. Biochemical and cell based measurements resolve that approximately 0.2% of the total calcineurin activity in cardiomyocytes is associated with AKAP150. Electrophysiological analyses establish that formation of this AKAP150-calcineurin signaling dyad is essential for the activation of the phosphatase and the subsequent down-regulation of Kv channel currents following MI. Thus AKAP150-mediated targeting of calcineurin to sarcolemmal micro-domains in ventricular myocytes contributes to the local and acute gene remodeling events that lead to the down-regulation of Kv currents.
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    • "AKAP79/150 (also know as AKAP5) is a family of three orthologs: murine AKAP150, bovine AKAP75 and human AKAP79 [5] [33]. It is a widely expressed anchoring protein that interacts with PKA, protein kinase C (PKC), the phosphatase calcineurin (CaN), calmodulin (CaM) as well as other signaling molecules [34] [35] [36]. "
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    ABSTRACT: Heart and blood vessels ensure adequate perfusion of peripheral organs with blood and nutrients. Alteration of the homeostatic functions of the cardiovascular system can cause hypertension, atherosclerosis, and coronary artery disease leading to heart injury and failure. A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that are crucially involved in modulating the function of the cardiovascular system both under physiological and pathological conditions. AKAPs assemble multifunctional signaling complexes that ensure correct targeting of the cAMP-dependent protein kinase (PKA) as well as other signaling enzymes to precise subcellular compartments. This allows local regulation of specific effector proteins that control the function of vascular and cardiac cells. This review will focus on recent advances illustrating the role of AKAPs in cardiovascular pathophysiology. The accent will be mainly placed on the molecular events linked to the control of vascular integrity and blood pressure as well as on the cardiac remodeling process associated with heart failure.
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    • "Both compounds are widely used as immunosuppressants in the clinic, mainly in organ transplantation and dermatology. In addition, there are several endogenous calcineurin inhibitors such as Down's syndrome candidate region 1 (DSCR1), calcineurin-binding protein 1 (CABIN1) and A-kinase anchor protein 79 (AKAP79) [29] [30] [31]. Interestingly, DSCR1 is upregulated in patients with Down's syndrome, and these patients are less predisposed to malignancy [32]. "
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