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AKAP signalling complexes: focal points in space and time

Key Points

  • A-kinase anchoring proteins (AKAPs) target protein kinase A (PKA) to distinct subcellular locations. This positions the enzyme at regions of cyclic-AMP production and confines phosphorylation to a subset of potential substrates.

  • Several AKAPs might be targeted to the same subcellular compartment, whereas splice variants of the same AKAP gene can be differentially targeted.

  • AKAPs often form complexes that include both signal-transduction and signal-termination enzymes. This therefore generates a locus to regulate the forward and backward steps of a given signalling process.

  • As the list of AKAP-binding partners increases, it is apparent that a single anchoring protein can interact with only a subset of its possible interacting proteins. Consequently, each anchoring protein has the potential to organize different enzyme combinations in a context-specific manner.

  • An emerging theme in AKAP regulation is the dynamic reorganization of the composition and function of AKAP signalling complexes. The recruitment or release of AKAP-binding partners can alter the response to incoming signals or change the location of a signalling complex.

  • Protein phosphorylation can relocalize, regulate, recruit or release AKAP-binding partners.

Abstract

Multiprotein signalling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize various enzymes that are regulated by second messengers.

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Figure 1: Cyclic AMP signalling pathways.
Figure 2: AKAP signalling complexes create focal points for signal transduction.
Figure 3: Tissue-specific AKAP complexes.
Figure 4: Substrate-specific AKAP complexes.
Figure 5: A cyclic AMP signalling module that is maintained by mAKAP.
Figure 6: AKAP-Lbc and Rho signalling.
Figure 7: Activation and release of protein kinase D (PKD) from the AKAP-Lbc complex.
Figure 8: Downregulation of the β2-adrenergic-receptor–gravin complex.

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Acknowledgements

We thank members of the Scott laboratory for their critical evaluation of the manuscript and L. Langeberg for her assistance with the figures and images. This work was supported by a fellowship from the Heart and Stroke Foundation of Canada to W.W. and by a National Institutes of Health grant to J.D.S.

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DATABASES

Swiss-Prot

Abi1

AKAP6

AKAP18

AKAP79

AKAP220

AKAP350

β2-AR

BAD

D-AKAP1

D-AKAP2

GluR1

gravin

KCNQ1

KCNQ2

mAKAP

MAP2

MDM2

NR1

NR2B

PIR121

PKCε

Rab32

WAVE1

WAVE2

WAVE3

WRP

Glossary

SCAFFOLD PROTEINS

Proteins that augment cellular responses by recruiting other proteins to a complex/scaffold. They usually contain several protein–protein-interaction domains.

G-PROTEIN-COUPLED RECEPTOR

(GPCR). A seven-helix transmembrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

HETEROTRIMERIC G PROTEIN

A protein complex of three proteins (Gα, Gβ and Gγ) Whereas Gβ and Gγ form a tight complex, Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

CYCLIC-NUCLEOTIDE-GATED CHANNEL

(CNGC). Conserved protein family with six predicted transmembrane helices that can form cation-conducting channels and is activated by the binding of cyclic nucleotides such as cAMP and cGMP.

PHOSPHODIESTERASES

Enzymes that can hydrolyse cAMP to 5′-AMP.

HOLOENZYME

An enzyme that consists of more than one subunit, each of which usually carries out a different function. Holoenzymes often exist as more than one isoform.

CG-NAP

Centrosome-and-Golgi-localized protein-kinase-N-associated protein.

CENTROSOME

The main microtubule-organizing centre of animal cells.

POSTSYNAPTIC DENSITY

(PSD). A multiprotein complex that contains the membrane, regulatory and scaffolding proteins that are required for efficient synaptic signalling in the postsynaptic neuron. It is particularly enriched in cytoskeletal proteins, which renders this complex resistant to solubilization by non-ionic detergents. In electron-microscopy preparations, this structure appears as an electron-dense region on the cytoplasmic face of the postsynaptic membrane.

DENDRITIC SPINES

Knob-like extensions of the dendritic surface which can receive synaptic input. The actin cytoskeleton within these structures undergoes constant remodelling, thereby giving rise to dynamic changes in the shape of dendritic spines.

NEUROMUSCULAR JUNCTION

(NMJ). The place of contact between the terminal of a motor neuron and the membrane of a muscle fibre. Nerve impulses are transmitted across the gap by diffusion of a transmitter.

GTPase-ACTIVATING PROTEIN

(GAP). Proteins that inactivate small GTP-binding proteins, such as Ras-family members, by increasing their rate of GTP hydrolysis.

ARP2/3 COMPLEX

A complex that consists of two actin-related proteins, Arp2 and Arp3, along with five smaller proteins. When activated, the Arp2/3 complex binds to the side of an existing actin filament and nucleates the assembly of a new actin filament. The resulting branch structure is Y-shaped.

LAMELLIPODIA

Thin, flat extensions at the cell periphery that are filled with a branching meshwork of actin filaments.

STRESS FIBRE

Also known as 'actin microfilament bundles'. These are bundles of parallel filaments that contain F-actin and other contractile molecules, which often stretch between cell attachments as if under stress.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

(GEF). A protein that facilitates the exchange of GDP (guanine diphosphate) for GTP (guanine triphosphate) in the nucleotide-binding pocket of a GTP-binding protein.

UBIQUITIN PROTEIN LIGASE (E3)

An enzyme that functions together with a ubiquitin-conjugating enzyme (E2) to couple the small protein ubiquitin to Lys residues on a target protein, which marks that protein for destruction by the proteasome.

M CURRENT

A cationic current that is suppressed by the activation of muscarinic receptors and that participates in determining the sub-threshold excitability of neurons and their responsiveness to synaptic input.

MUSCARINIC RECEPTORS

Acetylcholine GPCRs that are activated by the prototypical agonist, muscarine, a compound isolated from the mushroom Amanita muscaria.

MYRISTOYLATION

The covalent attachment of a hydrophobic myristoyl group to the N-terminal glycine residue of a nascent polypeptide.

PALMITOYLATION

The covalent attachment of a palmitate (16-carbon, saturated fatty acid) to a cysteine residue through a thioester bond.

VMAX

The maximal rate of enzymatic activity.

RNA INTERFERENCE

(RNAi). A form of post-transcriptional gene silencing in which expression or transfection of double-stranded RNA induces degradation, by nucleases, of the homologous endogenous transcripts, which mimics the effect of the reduction, or loss, of gene activity.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). The non-radiative transfer of energy from a donor fluorophore to an acceptor fluorophore that is typically <80 Å away. FRET will only occur between fluorophores in which the emission spectrum of the donor has a significant overlap with the excitation of the acceptor.

MULTIPLEX IMAGING WITH QUANTUM DOTS

A method that allows the simultaneous imaging of multiple events in a single cell by attaching quantum dots of different sizes to different molecules (such as antibodies). Quantum dots are inorganic fluorescent nanocrystals with a broad excitation spectrum and a narrow emission spectrum. A mixture of quantum dots of different sizes that is excited using one wavelength will yield multiple fluorescent signals at discrete wavelengths.

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Wong, W., Scott, J. AKAP signalling complexes: focal points in space and time. Nat Rev Mol Cell Biol 5, 959–970 (2004). https://doi.org/10.1038/nrm1527

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