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Targeting protein-protein interactions in complexes organized by A kinase anchoring proteins.

Calejo AI, Taskén K - Front Pharmacol (2015)

Bottom Line: AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways.Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role.Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Centre, University of Oslo Oslo, Norway ; Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital Oslo, Norway.

ABSTRACT
Cyclic AMP is a ubiquitous intracellular second messenger involved in the regulation of a wide variety of cellular processes, a majority of which act through the cAMP - protein kinase A (PKA) signaling pathway and involve PKA phosphorylation of specific substrates. PKA phosphorylation events are typically spatially restricted and temporally well controlled. A-kinase anchoring proteins (AKAPs) directly bind PKA and recruit it to specific subcellular loci targeting the kinase activity toward particular substrates, and thereby provide discrete spatiotemporal control of downstream phosphorylation events. AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways. Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role. Furthermore, development of novel classes of small molecules involved in displacement of AKAP-bound signal molecules is now emerging. Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of cAMP signaling pathways. Stimulation of G-protein-coupled receptors leads to activation of adenylyl cyclase (AC), which converts ATP into cAMP. cAMP increases in local microdomains and binds to different effectors such as protein kinase A (PKA), cyclic nucleotide gated ion channels and exchange protein directly activated by cAMP (Epac) leading to specific downstream effects. Cyclic nucleotide phosphodiesterases (PDEs) hydrolyse cAMP into AMP and terminates the signal. A-kinase anchoring proteins (AKAPs) anchor the signaling molecules involved in the pathway and target them to specific organelles in the cell.
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Figure 1: Schematic illustration of cAMP signaling pathways. Stimulation of G-protein-coupled receptors leads to activation of adenylyl cyclase (AC), which converts ATP into cAMP. cAMP increases in local microdomains and binds to different effectors such as protein kinase A (PKA), cyclic nucleotide gated ion channels and exchange protein directly activated by cAMP (Epac) leading to specific downstream effects. Cyclic nucleotide phosphodiesterases (PDEs) hydrolyse cAMP into AMP and terminates the signal. A-kinase anchoring proteins (AKAPs) anchor the signaling molecules involved in the pathway and target them to specific organelles in the cell.

Mentions: Intracellular 3′-5′-cyclic adenosine monophosphate (cAMP) is an important second messenger that regulates a number of biological processes. Even though cAMP is diffusible, its concentration and signaling are tightly controlled and coordinated through the involvement of a molecular machinery coordinating the spatial and temporal processes of localized cAMP signaling events. Signal transduction through the cAMP pathway starts by stimulation of G-protein-coupled-receptors (GPCRs), via specific extracellular ligands leading to activation of adenylyl cyclase (AC), which converts ATP into cAMP. The rise in intracellular cAMP levels leads to a set of events mediated by specific effector molecules, hereunder protein kinase A (PKA; Walsh et al., 1968), cyclic nucleotide gated ion channels (Brown et al., 1979) and exchange protein directly activated by cAMP (Epac; de Rooij et al., 1998; Kawasaki et al., 1998). To terminate the signal, intracellular cAMP levels must be brought back to basal levels; this is attained by cyclic nucleotide phosphodiesterases (PDEs), which hydrolyse cAMP and/or cGMP. Additionally, cAMP signalosomes targeted to specific subcellular locales by A-kinase anchoring proteins (AKAPs) bring together signal initiators, effector and terminators in supramolecular signaling complexes. The existence of these specific complexes (illustrated in Figure 1) governed by protein–protein interactions (PPIs) creates an opportunity for new therapeutic strategies to control cAMP dependent signaling that is out of tune or involved in pathologies. In this review we will first focus on signaling through AKAP-coordinated complexes, next on targeting PPIs as a possible strategy to control and regulate cAMP signaling events and finally mention a few examples of possible PPIs that could be targeted. We will discuss cAMP/PKA/AKAP signaling in general terms but will particularly focus on the heart, where cAMP signaling pathways are involved in different stages of the cardiac cycle and in several pathologies.


Targeting protein-protein interactions in complexes organized by A kinase anchoring proteins.

Calejo AI, Taskén K - Front Pharmacol (2015)

Schematic illustration of cAMP signaling pathways. Stimulation of G-protein-coupled receptors leads to activation of adenylyl cyclase (AC), which converts ATP into cAMP. cAMP increases in local microdomains and binds to different effectors such as protein kinase A (PKA), cyclic nucleotide gated ion channels and exchange protein directly activated by cAMP (Epac) leading to specific downstream effects. Cyclic nucleotide phosphodiesterases (PDEs) hydrolyse cAMP into AMP and terminates the signal. A-kinase anchoring proteins (AKAPs) anchor the signaling molecules involved in the pathway and target them to specific organelles in the cell.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562273&req=5

Figure 1: Schematic illustration of cAMP signaling pathways. Stimulation of G-protein-coupled receptors leads to activation of adenylyl cyclase (AC), which converts ATP into cAMP. cAMP increases in local microdomains and binds to different effectors such as protein kinase A (PKA), cyclic nucleotide gated ion channels and exchange protein directly activated by cAMP (Epac) leading to specific downstream effects. Cyclic nucleotide phosphodiesterases (PDEs) hydrolyse cAMP into AMP and terminates the signal. A-kinase anchoring proteins (AKAPs) anchor the signaling molecules involved in the pathway and target them to specific organelles in the cell.
Mentions: Intracellular 3′-5′-cyclic adenosine monophosphate (cAMP) is an important second messenger that regulates a number of biological processes. Even though cAMP is diffusible, its concentration and signaling are tightly controlled and coordinated through the involvement of a molecular machinery coordinating the spatial and temporal processes of localized cAMP signaling events. Signal transduction through the cAMP pathway starts by stimulation of G-protein-coupled-receptors (GPCRs), via specific extracellular ligands leading to activation of adenylyl cyclase (AC), which converts ATP into cAMP. The rise in intracellular cAMP levels leads to a set of events mediated by specific effector molecules, hereunder protein kinase A (PKA; Walsh et al., 1968), cyclic nucleotide gated ion channels (Brown et al., 1979) and exchange protein directly activated by cAMP (Epac; de Rooij et al., 1998; Kawasaki et al., 1998). To terminate the signal, intracellular cAMP levels must be brought back to basal levels; this is attained by cyclic nucleotide phosphodiesterases (PDEs), which hydrolyse cAMP and/or cGMP. Additionally, cAMP signalosomes targeted to specific subcellular locales by A-kinase anchoring proteins (AKAPs) bring together signal initiators, effector and terminators in supramolecular signaling complexes. The existence of these specific complexes (illustrated in Figure 1) governed by protein–protein interactions (PPIs) creates an opportunity for new therapeutic strategies to control cAMP dependent signaling that is out of tune or involved in pathologies. In this review we will first focus on signaling through AKAP-coordinated complexes, next on targeting PPIs as a possible strategy to control and regulate cAMP signaling events and finally mention a few examples of possible PPIs that could be targeted. We will discuss cAMP/PKA/AKAP signaling in general terms but will particularly focus on the heart, where cAMP signaling pathways are involved in different stages of the cardiac cycle and in several pathologies.

Bottom Line: AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways.Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role.Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Centre, University of Oslo Oslo, Norway ; Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital Oslo, Norway.

ABSTRACT
Cyclic AMP is a ubiquitous intracellular second messenger involved in the regulation of a wide variety of cellular processes, a majority of which act through the cAMP - protein kinase A (PKA) signaling pathway and involve PKA phosphorylation of specific substrates. PKA phosphorylation events are typically spatially restricted and temporally well controlled. A-kinase anchoring proteins (AKAPs) directly bind PKA and recruit it to specific subcellular loci targeting the kinase activity toward particular substrates, and thereby provide discrete spatiotemporal control of downstream phosphorylation events. AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways. Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role. Furthermore, development of novel classes of small molecules involved in displacement of AKAP-bound signal molecules is now emerging. Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart.

No MeSH data available.


Related in: MedlinePlus