Mechanisms of Protein Kinase A Anchoring

doi:10.1016/S1937-6448(10)83005-9

International Review of Cell and Molecular Biology

Volume 283, 2010, Pages 235-330

https://doi.org/10.1016/S1937-6448(10)83005-9 Get rights and content

Abstract

The second messenger cyclic adenosine monophosphate (cAMP), which is produced by adenylyl cyclases following stimulation of G-protein-coupled receptors, exerts its effect mainly through the cAMP-dependent serine/threonine protein kinase A (PKA). Due to the ubiquitous nature of the cAMP/PKA system, PKA signaling pathways underlie strict spatial and temporal control to achieve specificity. A-kinase anchoring proteins (AKAPs) bind to the regulatory subunit dimer of the tetrameric PKA holoenzyme and thereby target PKA to defined cellular compartments in the vicinity of its substrates. AKAPs promote the termination of cAMP signals by recruiting phosphodiesterases and protein phosphatases, and the integration of signaling pathways by binding additional signaling proteins. AKAPs are a heterogeneous family of proteins that only display similarity within their PKA-binding domains, amphipathic helixes docking into a hydrophobic groove formed by the PKA regulatory subunit dimer. This review summarizes the current state of information on compartmentalized cAMP/PKA signaling with a major focus on structural aspects, evolution, diversity, and (patho)physiological functions of AKAPs and intends to outline newly emerging directions of the field, such as the elucidation of AKAP mutations and alterations of AKAP expression in human diseases, and the validation of AKAP-dependent protein–protein interactions as new drug targets. In addition, alternative PKA anchoring mechanisms employed by noncanonical AKAPs and PKA catalytic subunit-interacting proteins are illustrated.

Introduction

Extracellular stimuli as diverse as hormones, growth factors, cytokines, sensory inputs, or pathogens trigger intracellular signal transduction events to elicit specific responses. All signal transduction processes involving the second messenger cyclic adenosine monophosphate (cAMP) depend upon a similar core of molecular components. Cell-type-specific expression of different isoforms of these components together with a unique complement of scaffolding proteins that assemble spatially discrete signaling complexes facilitates specific regulation of cell functions. The molecular “toolbox” that allows for this comprises adenylyl cyclases (ACs), which generate cAMP, and phosphodiesterases (PDEs) degrading it. Together, ACs and PDEs not only determine the level of cAMP in cells but, through the defined spatial sequestration of specific isoforms of each of these enzymes, they also generate gradients of cAMP at specific cellular sites. These gradients of cAMP have to be interpreted locally and this role is undertaken by protein kinase A (PKA), exchange proteins activated by cAMP (Epacs) acting as GTP exchange factors and, in a few cell types, cyclic nucleotide gated ion channels (CNGs). The interpretation of signals at discrete cellular locations is achieved by sequestration of these cAMP effectors to particular signaling nodes, of which A-kinase anchoring proteins (AKAPs) play a major role. They direct PKA to specific cellular sites into close proximity of downstream substrates. Also, a specific subset of PDEs, which provide the sole means of degrading cAMP in cells, are sequestered by AKAPs. This enables these PDEs to gate the threshold for activation of tethered PKA by controlling cAMP concentrations locally. The more than 40 members of the diverse family of AKAPs are expressed in a cell- and organelle-specific fashion and not only tether PKA and PDEs but also interact with G-protein-coupled receptors (GPCRs), ACs, Epacs, and PKA substrates, thereby regulating cAMP signaling at all levels: cAMP generation, control of cAMP effectors, and cAMP signal termination (Fig. 5.1). In addition, AKAPs are platforms for the integration of cAMP and other signaling pathways as they can bind further protein kinases, protein phosphatases (PPs), ion channels, and small GTP-binding proteins (Fig. 5.1). Moreover, AKAPs may provide novel targets for therapeutic intervention as the dysregulation of compartmentalized cAMP signaling is associated with human disease.

Section snippets

Adenylyl cyclases

There are 10 human isoforms of ACs: 9 plasma membrane resident (AC1–AC9) and 1 soluble AC (sAC). AC1–AC9 are transmembrane proteins that are stimulated by Gα_s subunits of heterotrimeric G proteins upon activation of GPCRs. Additionally, ACs can be regulated by Gβγ and Gα_i subunits of G proteins, Ca²⁺, and protein kinases (Cooper 2005, Sunahara 2002, Willoughby 2007). sAC is abundantly expressed in sperm and activated by bicarbonate. sAC generates the cAMP necessary for sperm capacitation and is

AKAPs: Scaffolds for Local Signaling

PKA is recruited to intracellular domains by AKAPs, a family of scaffolding proteins with more than 40 members. AKAPs were first found as contaminants in purifications of RII subunits (Theurkauf and Vallee, 1982). More members of the AKAP family were identified by using radioactively labeled RII subunits as probes in far-western blotting assays (RII overlays; Lohmann et al., 1984). The unifying feature of AKAPs is the presence of a PKA-binding domain, also termed RII-binding domain (RIIBD)

Cellular Functions Regulated by AKAP-Anchored PKA

AKAPs regulate important functions in every human cell. Prime examples are synaptic plasticity (Dell'Acqua et al., 2006), sperm motility (Carr and Newell, 2007), T-cell immune responses (Torgersen et al., 2008) and several exocytic processes (Szaszak et al., 2008). As an example for the ability of AKAPs to integrate cellular signaling, we will outline the link between PKA and GSK3β established by several AKAPs and other scaffolding proteins in the following section. In following sections, we

Lessons from AKAP KO mouse models

KO and mutant mouse models are invaluable tools to study in vivo protein function in a mammalian system. Several genes encoding AKAPs were disrupted or mutated, resulting in diverse phenotypes. These are summarized in Table 5.5.

Other reviews analyzed the KO models for AKAP149/AKAP1, AKAP4, AKAP150/AKAP5, mAKAPα/AKAP6, WAVE-1, MAP2, and Ezrin (Carnegie et al., 2009, Hundsrucker & Klussmann, 2008, Kirschner et al., 2009, Mauban et al., 2009, Welch et al., 2010). Here, we focus on recently

Concluding Remarks

Apart from their similarities in PKA binding, AKAPs are a highly diverse family of proteins, anchoring PKA to most organelles. By binding components of the cAMP signaling machinery such as GPCRs, ACs, and PDEs, AKAPs are crucial for the spatial and temporal control of cAMP/PKA signaling. This facilitates specific responses to multiple cAMP-elevating stimuli. While the vast majority of PKA-interacting proteins are canonical AKAPs that bind to the PKA regulatory subunit dimer via an amphipathic

Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft (Kl1415/3-2 and 4-2) and the GoBio program of the Bundesministerium für Bildung und Forschung (FKZ 0315516).

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Chapter Five - Mechanisms of Protein Kinase A Anchoring

Abstract

Introduction

Section snippets

Adenylyl cyclases

AKAPs: Scaffolds for Local Signaling

Cellular Functions Regulated by AKAP-Anchored PKA

Lessons from AKAP KO mouse models

Concluding Remarks

Acknowledgments

Prog. Brain Res.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Curr. Opin. Chem. Biol.

J. Biol. Chem.

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J. Biol. Chem.

J. Mol. Biol.

Trends Cardiovasc. Med.

Neuropharmacology

Mol. Cell

Exp. Eye Res.

Mol. Cell. Neurosci.

J. Lipid Res.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Neuron

Mol. Cell

J. Mol. Biol.

J. Biol. Chem.

Mol. Cell

Mol. Cell

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J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Dev. Biol.

J. Biol. Chem.

Eur. J. Cell Biol.

Am. J. Med.

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J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Neuropeptides

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Cell Biol.

Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56δ subunit

Proc. Natl. Acad. Sci. USA

The role of kinases in the Hedgehog signalling pathway

EMBO Rep.

Loss of the SSeCKS/Gravin/AKAP12 gene results in prostatic hyperplasia

Cancer Res.

Glycogen synthase kinase-3: properties, functions, and regulation

Chem. Rev.

Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics

J. Cell Biol.