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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sutherland, E. W. & Rall, T. W. Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J. Biol. Chem. 232, 1077–1091 (1958).
Bar, H. P. & Hechter, O. Adenyl cyclase and hormone action. I. Effects of adrenocorticotropic hormone, glucagon, and epinephrine on the plasma membrane of rat fat cells. Proc. Natl Acad. Sci. USA 63, 350–356 (1969).
Pierce, K. L., Premont, R. T. & Lefkowitz, R. J. Seven-transmembrane receptors. Nature Rev. Mol. Cell Biol. 3, 639–650 (2002).
Levitzki, A. From epinephrine to cyclic AMP. Science 241, 800–806 (1988).
Kasai, H. & Petersen, O. H. Spatial dynamics of second messengers: IP3 and cAMP as long-range and associative messengers. Trends Neurosci. 17, 95–101 (1994).
Barsony, J. & Marks, S. J. Immunocytology on microwave-fixed cells reveals rapid and agonist-specific changes in subcellular accumulation patterns for cAMP or cGMP. Proc. Natl Acad. Sci. USA 87, 1188–1192 (1990).
Bacskai, B. J. et al. Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons. Science 260, 222–226 (1993).
Zaccolo, M. & Pozzan, T. Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295, 1711–1715 (2002). An elegant study to visualize cAMP dynamics in primary mammalian cells using physiologically relevant stimuli in real time.
Kaupp, U. B. & Seifert, R. Cyclic nucleotide-gated ion channels. Physiol. Rev. 82, 769–824 (2002).
Houslay, M. D. & Adams, D. R. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem. J. 370, 1–18 (2003).
Bos, J. L. Epac: a new cAMP target and new avenues in cAMP research. Nature Rev. Mol. Cell Biol. 4, 733–738 (2003).
Walsh, D. A., Perkins, J. P. & Krebs, E. G. An adenosine 3′,5′-monophosphate-dependent protein kinase from rabbit skeletal muscle. J. Biol. Chem. 243, 3763–3765 (1968).
Corbin, J. D., Soderling, T. R. & Park, C. R. Regulation of adenosine 3′,5′-monophosphate-dependent protein kinase. J. Biol. Chem. 248, 1813–1821 (1973).
Corbin, J. D. & Keely, S. L. Characterization and regulation of heart adenosine 3′:5′- monophosphate-dependent protein kinase isozymes. J. Biol. Chem. 252, 910–918 (1977).
Potter, R. L. & Taylor, S. S. Relationships between structural domains and function in the regulatory subunit of cAMP-dependent protein kinases I and II from porcine skeletal muscle. J. Biol. Chem. 254, 2413–2418 (1979).
Lee, D. C., Carmichael, D. F., Krebs, E. G. & McKnight, G. S. Isolation of cDNA clone for the type I regulatory subunit of bovine cAMP-dependent protein kinase. Proc. Natl Acad. Sci. USA 80, 3608–3612 (1983).
Scott, J. D. et al. The molecular cloning of a type II regulatory subunit of the cAMP-dependent protein kinase from rat skeletal muscle and mouse brain. Proc. Natl Acad. Sci. USA 84, 5192–5196 (1987).
Scott, J. D. et al. Type II regulatory subunit dimerization determines the subcellular localization of the cAMP-dependent protein kinase. J. Biol. Chem. 265, 21561–21566 (1990).
Carnegie, G. K. & Scott, J. D. A-kinase anchoring proteins and neuronal signaling mechanisms. Genes Dev. 17, 1557–1568 (2003).
Lohmann, S. M., De Camilli, P., Einig, I. & Walter, U. High-affinity binding of the regulatory subunit (RII) of cAMP-dependent protein kinase to microtubule-associated and other cellular proteins. Proc. Natl Acad. Sci. USA 81, 6723–6727 (1984). Introduction of the RII overlay procedure, a widely used in vitro assay used to discover novel AKAPs.
Carr, D. W. et al. Interaction of the regulatory subunit (RII) of cAMP-dependent protein kinase with RII-anchoring proteins occurs through an amphipathic helix binding motif. J. Biol. Chem. 266, 14188–14192 (1991). Identified an amphipathic helical structure as the key determinant for RII binding.
Newlon, M. G., Roy, M., Hausken, Z. E., Scott, J. D. & Jennings, P. A. The A-kinase anchoring domain of type IIα cAMP-dependent protein kinase is highly helical. J. Biol. Chem. 272, 23637–23644 (1997).
Newlon, M. G. et al. A novel mechanism of PKA anchoring revealed by solution structures of anchoring complexes. EMBO J. 20, 1651–1662 (2001).
Newlon, M. G. et al. The molecular basis for protein kinase A anchoring revealed by solution NMR. Nature Struct. Biol. 6, 222–227 (1999).
Angelo, R. & Rubin, C. S. Molecular characterization of an anchor protein (AKAPCE) that binds the RI subunit (RCE) of type I protein kinase A from Caenorhabditis elegans. J. Biol. Chem. 273, 14633–14643 (1998).
Huang, L. J., Durick, K., Weiner, J. A., Chun, J. & Taylor, S. S. Identification of a novel dual specificity protein kinase A anchoring protein, D-AKAP1. J. Biol. Chem. 272, 8057–8064 (1997).
Wang, L. et al. Cloning and mitochondrial localization of full-length D-AKAP2, a protein kinase A anchoring protein. Proc. Natl Acad. Sci. USA 98, 3220–3225 (2001).
Carr, D. W., Hausken, Z. E., Fraser, I. D., Stofko-Hahn, R. E. & Scott, J. D. Association of the type II cAMP-dependent protein kinase with a human thyroid RII-anchoring protein. Cloning and characterization of the RII-binding domain. J. Biol. Chem. 267, 13376–13382 (1992).
Alto, N. M. et al. Bioinformatic design of A-kinase anchoring protein-in silico: a potent and selective peptide antagonist of type II protein kinase A anchoring. Proc. Natl Acad. Sci. USA 100, 4445–4450 (2003).
Burns-Hamuro, L. L. et al. Designing isoform-specific peptide disruptors of protein kinase A localization. Proc. Natl Acad. Sci. USA 100, 4072–4077 (2003). References 29 and 30 show that it is possible to design peptides that selectively disrupt R-subunit–AKAP interactions.
Dell'Acqua, M. L., Faux, M. C., Thorburn, J., Thorburn, A. & Scott, J. D. Membrane-targeting sequences on AKAP79 bind phosphatidylinositol-4,5-bisphosphate. EMBO J. 17, 2246–2260 (1998).
Malbon, C. C., Tao, J. & Wang, H. Y. AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes. Biochem. J. 379, 1–9 (2004).
Trotter, K. W. et al. Alternative splicing regulates the subcellular localization of A-kinase anchoring protein 18 isoforms. J. Cell Biol. 147, 1481–1492 (1999).
Huang, L. J. et al. NH2-terminal targeting motifs direct dual specificity A-kinase-anchoring protein 1 (D-AKAP1) to either mitochondria or endoplasmic reticulum. J. Cell Biol. 145, 951–959 (1999).
Alto, N. M., Soderling, J. & Scott, J. D. Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics. J. Cell Biol. 158, 659–668 (2002).
Danial, N. N. et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952–956 (2003).
Diviani, D., Langeberg, L. K., Doxsey, S. J. & Scott, J. D. Pericentrin anchors protein kinase A at the centrosome through a newly identified RII-binding domain. Curr. Biol. 10, 417–420 (2000).
Gillingham, A. K. & Munro, S. The PACT domain, a conserved centrosomal targeting motif in the coiled-coil proteins AKAP450 and pericentrin. EMBO Rep. 1, 524–529 (2000).
Westphal, R. S. et al. Regulation of NMDA receptors by an associated phosphatase–kinase signaling complex. Science 285, 93–96 (1999).
Schmidt, P. H. et al. AKAP350: a multiply spliced A-kinase anchoring protein associated with centrosomes. J. Biol. Chem. 274, 3055–3066 (1999).
Witczak, O. et al. Cloning and characterization of a cDNA encoding an A-kinase anchoring protein located in the centrosome, AKAP450. EMBO J. 18, 1858–1868 (1999).
Fraser, I. D. et al. A novel lipid-anchored A-kinase anchoring protein facilitates cAMP- responsive membrane events. EMBO J. 17, 2261–2272 (1998).
Bregman, D. B., Hirsch, A. H. & Rubin, C. S. Molecular characterization of bovine brain P75, a high affinity binding protein for the regulatory subunit of cAMP-dependent protein kinase IIβ. J. Biol. Chem. 266, 7207–7213 (1991).
Carr, D. W., Stofko-Hahn, R. E., Fraser, I. D. C., Cone, R. D. & Scott, J. D. Localization of the cAMP-dependent protein kinase to the postsynaptic densities by A-kinase anchoring proteins: characterization of AKAP79. J. Biol. Chem. 24, 16816–16823 (1992).
Coghlan, V. M. et al. Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. Science 267, 108–112 (1995).
Klauck, T. M. et al. Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 271, 1589–1592 (1996). The first demonstration of a multivalent AKAP complex — in particular, one that contains a signalling molecule from a distinct pathway (PKC) and a signal-termination enzyme.
Faux, M. C. & Scott, J. D. Molecular glue: kinase anchoring and scaffold proteins. Cell 70, 8–12 (1996).
Faux, M. C. et al. Mechanism of A-kinase-anchoring protein 79 (AKAP79) and protein kinase C interaction. Biochem. J. 343, 443–452 (1999).
Fraser, I. D. & Scott, J. D. Modulation of ion channels: a 'current' view of AKAPs. Neuron 23, 423–426 (1999).
Gao, T. et al. cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits. Neuron 19, 185–196 (1997).
Jo, I. et al. AQP2 is a substrate for endogenous PP2B activity within an inner medullary AKAP-signaling complex. Am. J. Physiol. Renal Physiol. 281, F958–F965 (2001).
Potet, F., Scott, J. D., Mohammad-Panah, R., Escande, D. & Baro, I. I. AKAP proteins anchor cAMP-dependent protein kinase to KvLQT1/IsK channel complex. Am. J. Physiol. Heart Circ. Physiol. 280, H2038–H2045 (2001).
Nauert, J. B., Klauck, T. M., Langeberg, L. K. & Scott, J. D. Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Curr. Biol. 7, 52–62 (1997).
Takahashi, M. et al. Characterization of a novel giant scaffolding protein, CG-NAP, that anchors multiple signaling enzymes to centrosome and the Golgi apparatus. J. Biol. Chem. 274, 17267–17274 (1999).
Takahashi, M., Mukai, H., Oishi, K., Isagawa, T. & Ono, Y. Association of immature hypo-phosphorylated protein kinase Cε with an anchoring protein CG-NAP. J. Biol. Chem. 275, 34592–34596 (2000).
Sillibourne, J. E., Milne, D. M., Takahashi, M., Ono, Y. & Meek, D. W. Centrosomal anchoring of the protein kinase CK1δ mediated by attachment to the large, coiled-coil scaffolding protein CG-NAP/AKAP450. J. Mol. Biol. 322, 785–797 (2002).
Schillace, R. V. & Scott, J. D. Association of the type 1 protein phosphatase PP1 with the A-kinase anchoring protein AKAP220. Curr. Biol. 9, 321–324 (1999).
Tanji, C. et al. A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3β (GSK-3β) and mediates protein kinase A-dependent inhibition of GSK-3β. J. Biol. Chem. 277, 36955–36961 (2002).
Miki, H., Suetsugu, S. & Takenawa, T. WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. EMBO J. 17, 6932–6941 (1998).
Westphal, R. S., Soderling, S. H., Alto, N. M., Langeberg, L. K. & Scott, J. D. Scar/WAVE-1, a Wiskott–Aldrich syndrome protein, assembles an actin-associated multi-kinase scaffold. EMBO J. 19, 4589–4600 (2000).
Soderling, S. H. et al. The WRP component of the WAVE-1 complex attenuates Rac-mediated signalling. Nature Cell Biol. 4, 970–975 (2002).
Machesky, L. M. & Insall, R. H. Scar1 and the related Wiskott–Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex. Curr. Biol. 8, 1347–1356 (1998).
Diviani, D., Soderling, J. & Scott, J. D. AKAP-Lbc anchors protein kinase A and nucleates Gα12-selective Rho-mediated stress fiber formation. J. Biol. Chem. 276, 44247–44257 (2001).
Shih, M., Lin, F., Scott, J. D., Wang, H. Y. & Malbon, C. C. Dynamic complexes of β2-adrenergic receptors with protein kinases and phosphatases and the role of gravin. J. Biol. Chem. 274, 1588–1595 (1999).
Tao, J., Wang, H. Y. & Malbon, C. C. Protein kinase A regulates AKAP250 (gravin) scaffold binding to the β2-adrenergic receptor. EMBO J. 22, 6419–6429 (2003).
Eden, S., Rohatgi, R., Podtelejnikov, A. V., Mann, M. & Kirschner, M. W. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418, 790–793 (2002).
Innocenti, M. et al. Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nature Cell Biol. 6, 319–327 (2004).
Soderling, S. H. et al. Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice. Proc. Natl Acad. Sci. USA 100, 1723–1728 (2003). One of the first published reports on an AKAP-null mouse model, the phenotype of which implies that the WAVE1 scaffold is crucial for the development and function of the central nervous system.
Harada, H. et al. Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol. Cell 3, 413–422 (1999).
Marx, S. O. et al. Requirement of a macromolecular signaling complex for β adrenergic receptor modulation of the KCNQ1–KCNE1 potassium channel. Science 295, 496–499 (2002).
Tu, H., Tang, T. S., Wang, Z. & Bezprozvanny, I. Association of type 1 inositol 1,4,5-trisphosphate receptor with AKAP9 (Yotiao) and protein kinase A. J. Biol. Chem. 279, 19375–19382 (2004).
Shanks, R. A., Steadman, B. T., Schmidt, P. H. & Goldenring, J. R. AKAP350 at the Golgi apparatus. I. Identification of a distinct Golgi apparatus targeting motif in AKAP350. J. Biol. Chem. 277, 40967–40972 (2002).
Shanks, R. A. et al. AKAP350 at the Golgi apparatus. II. Association of AKAP350 with a novel chloride intracellular channel (CLIC) family member. J. Biol. Chem. 277, 40973–40980 (2002).
Takahashi, M., Yamagiwa, A., Nishimura, T., Mukai, H. & Ono, Y. Centrosomal proteins CG-NAP and kendrin provide microtubule nucleation sites by anchoring γ-tubulin ring complex. Mol. Biol. Cell 13, 3235–3245 (2002).
Greengard, P., Jen, J., Nairn, A. C. & Stevens, C. F. Enhancement of glutamate response by cAMP-dependent protein kinase in hippocampal neurons. Science 253, 1135–1138 (1991).
Jahr, C. E. & Lester, R. A. J. Synaptic excitation mediated by glutamate-gated ion channels. Curr. Opin. Neurobiol. 2, 395–400 (1992).
Colledge, M. et al. Targeting of PKA to glutamate receptors through a MAGUK–AKAP complex. Neuron 27, 107–119 (2000). Describes the molecular mechanism by which AKAP79/150-anchored PKA can modulate NMDA and AMPA receptors.
Tavalin, S. J. et al. Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares properties with long-term depression. J. Neurosci. 22, 3044–3051 (2002).
Kameyama, K., Lee, H. K., Bear, M. F. & Huganir, R. L. Involvement of a postsynaptic protein kinase A substrate in the expression of homosynaptic long-term depression. Neuron 21, 1163–1175 (1998).
Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F. & Huganir, R. L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).
Banke, T. G. et al. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J. Neurosci. 20, 89–102 (2000).
Blackstone, C., Murphy, T. H., Moss, S. J., Baraban, J. M. & Huganir, R. L. Cyclic AMP and synaptic activity-dependent phosphorylation of AMPA-preferring glutamate receptors. J. Neurosci. 14, 7585–7593 (1994).
Swope, S. L., Moss, S. I., Raymond, L. A. & Huganir, R. L. Regulation of ligand-gated ion channels by protein phosphorylation. Adv. Second Messenger Phosphoprotein Res. 33, 49–78 (1999).
Esteban, J. A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nature Neurosci. 6, 136–143 (2003).
Colledge, M. et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40, 595–607 (2003).
Jones, S. et al. Bradykinin excites rat sympathetic neurons by inhibition of M current through a mechanism involving B2 receptors and Gαq/11 . Neuron 14, 399–405 (1995).
Wang, H. S. & McKinnon, D. Potassium currents in rat prevertebral and paravertebral sympathetic neurones: control of firing properties. J. Physiol. 485, 319–335 (1995).
Suh, B. C. & Hille, B. Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron 35, 507–520 (2002).
Zhang, H. et al. PIP2 activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37, 963–975 (2003).
Mellor, H. & Parker, P. J. The extended protein kinase C superfamily. Biochem. J. 332, 281–292 (1998).
Bosma, M. M. & Hille, B. Protein kinase C is not necessary for peptide-induced suppression of M current or for desensitization of the peptide receptors. Proc. Natl Acad. Sci. USA 86, 2943–2947 (1989).
Cruzblanca, H., Koh, D. S. & Hille, B. Bradykinin inhibits M current via phospholipase C and Ca2+ release from IP3-sensitive Ca2+ stores in rat sympathetic neurons. Proc. Natl Acad. Sci. USA 95, 7151–7156 (1998).
Adams, P. R. & Brown, D. A. Luteinizing hormone-releasing factor and muscarinic agonists act on the same voltage-sensitive K+-current in bullfrog sympathetic neurones. Br. J. Pharmacol. 68, 353–355 (1980).
Hoshi, N. et al. AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. Nature Neurosci. 6, 564–571 (2003). Shows that AKAPs can organize signalling complexes that contain a subset of all the possible binding partners.
Hulme, J. T., Ahn, M., Hauschka, S. D., Scheuer, T. & Catterall, W. A. A novel leucine zipper targets AKAP15 and cyclic AMP-dependent protein kinase to the C terminus of the skeletal muscle Ca2+ channel and modulates its function. J. Biol. Chem. 277, 4079–4087 (2002).
Tibbs, V. C., Gray, P. C., Catterall, W. A. & Murphy, B. J. AKAP15 anchors cAMP-dependent protein kinase to brain sodium channels. J. Biol. Chem. 273, 25783–25788 (1998).
Dodge, K. L. et al. mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module. EMBO J. 20, 1921–1930 (2001). Describes a negative-feedback loop between PKA and a phosphodiesterase anchored to an AKAP.
Conti, M. Phosphodiesterases and cyclic nucleotide signaling in endocrine cells. Mol. Endocrinol. 14, 1317–1327 (2000).
Conti, M. et al. Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J. Biol. Chem. 278, 5493–5496 (2003).
Klussmann, E. et al. Ht31: the first protein kinase A anchoring protein to integrate protein kinase A and Rho signaling. FEBS Lett. 507, 264–268 (2001).
Diviani, D., Abuin, L., Cotecchia, S. & Pansier, L. Anchoring of both PKA and 14-3-3 inhibits the Rho-GEF activity of the AKAP-Lbc signaling complex. EMBO J. 23, 2811–2820 (2004).
Jin, J. et al. Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Curr. Biol. 14, 1436–1450 (2004). References 101 and 102 identify an inhibitory mechanism that downregulates the Rho-GEF activity of AKAP-Lbc, and provide the first example of an interaction between an AKAP and 14-3–3, a classic phosphoserine/threonine binding protein.
Mackintosh, C. Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes. Biochem. J. 381, 329–342 (2004).
Sette, C. & Conti, M. Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. J. Biol. Chem. 271, 16526–16534 (1996).
Carlisle Michel, J. J. et al. PKA phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signaling complex. Biochem. J. 381, 587–592 (2004).
Kapiloff, M. S., Jackson, N. & Airhart, N. mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope. J. Cell Sci. 114, 3167–3176 (2001).
Tasken, K. A. et al. Phosphodiesterase 4D and protein kinase A type II constitute a signaling unit in the centrosomal area. J. Biol. Chem. 276, 21999–22002 (2001).
Carnegie, G. K., Smith, F. D., McConnachie, G., Langeberg, L. K. & Scott, J. D. AKAP-Lbc nucleates a protein kinase D activation scaffold. Mol. Cell 15, 889–899 (2004).
Zugaza, J. L., Sinnett-Smith, J., Van Lint, J. & Rozengurt, E. Protein kinase D (PKD) activation in intact cells through a protein kinase C-dependent signal transduction pathway. EMBO J. 15, 6220–6230 (1996).
Schmidt, M. et al. A role for Rho in receptor- and G protein-stimulated phospholipase C. Reduction in phosphatidylinositol 4,5-bisphosphate by Clostridium difficile toxin B. Naunyn Schmiedebergs Arch. Pharmacol. 354, 87–94 (1996).
Rebecchi, M. J. & Pentyala, S. N. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol. Rev. 80, 1291–1335 (2000).
Oancea, E., Bezzerides, V. J., Greka, A. & Clapham, D. E. Mechanism of persistent protein kinase D1 translocation and activation. Dev. Cell 4, 561–574 (2003).
Marklund, U., Lightfoot, K. & Cantrell, D. Intracellular location and cell context-dependent function of protein kinase D. Immunity 19, 491–501 (2003).
Matthews, S. A., Iglesias, T., Rozengurt, E. & Cantrell, D. Spatial and temporal regulation of protein kinase D (PKD). EMBO J. 19, 2935–2945 (2000).
Waldron, R. T. et al. Activation loop Ser744 and Ser748 in protein kinase D are transphosphorylated in vivo. J. Biol. Chem. 276, 32606–32615 (2001).
Van Lint, J. et al. Protein kinase D: an intracellular traffic regulator on the move. Trends Cell Biol. 12, 193–200 (2002).
Lin, F., Wang, H. & Malbon, C. C. Gravin-mediated formation of signaling complexes in β2-adrenergic receptor desensitization and resensitization. J. Biol. Chem. 275, 19025–19034 (2000).
Fan, G., Shumay, E., Wang, H. & Malbon, C. C. The scaffold protein gravin (cAMP-dependent protein kinase-anchoring protein 250) binds the β2-adrenergic receptor via the receptor cytoplasmic Arg-329 to Leu-413 domain and provides a mobile scaffold during desensitization. J. Biol. Chem. 276, 24005–24014 (2001).
Shenoy, S. K., McDonald, P. H., Kohout, T. A. & Lefkowitz, R. J. Regulation of receptor fate by ubiquitination of activated β2-adrenergic receptor and β-arrestin. Science 294, 1307–1313 (2001).
Lester, L. B., Faux, M. C., Nauert, J. B. & Scott, J. D. Targeted protein kinase A and PP-2B regulate insulin secretion through reversible phosphorylation. Endocrinology 142, 1218–1227 (2001).
Schillace, R. V., Andrews, S. F., Liberty, G. A., Davey, M. P. & Carr, D. W. Identification and characterization of myeloid translocation gene 16b as a novel A kinase anchoring protein in T lymphocytes. J. Immunol. 168, 1590–1599 (2002).
Oliveria, S. F., Gomez, L. L. & Dell'Acqua, M. L. Imaging kinase–AKAP79–phosphatase scaffold complexes at the plasma membrane in living cells using FRET microscopy. J. Cell Biol. 160, 101–112 (2003).
Chan, W. C. et al. Luminescent quantum dots for multiplexed biological detection and imaging. Curr. Opin. Biotechnol. 13, 40–46 (2002).
Verkhusha, V. V. & Lukyanov, K. A. The molecular properties and applications of Anthozoa fluorescent proteins and chromoproteins. Nature Biotechnol. 22, 289–296 (2004).
Steen, R. L., Martins, S. B., Tasken, K. & Collas, P. Recruitment of protein phosphatase 1 to the nuclear envelope by A-kinase anchoring protein AKAP149 is a prerequisite for nuclear lamina assembly. J. Cell Biol. 150, 1251–1262 (2000).
Chen, D., Purohit, A., Halilovic, E., Doxsey, S. J. & Newton, A. C. Centrosomal anchoring of protein kinase C βII by pericentrin controls microtubule organization, spindle function, and cytokinesis. J. Biol. Chem. 279, 4829–4839 (2004).
Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).
Kapiloff, M. S., Schillace, R. V., Westphal, A. M. & Scott, J. D. mAKAP: an A-kinase anchoring protein targeted to the nuclear membrane of differentiated myocytes. J. Cell Sci. 112, 2725–2736 (1999).
Bregman, D. B., Bhattacharyya, N. & Rubin, C. S. High affinity binding protein for the regulatory subunit of cAMP-dependent protein kinase II-B. Cloning, characterization, and expression of cDNAs for rat brain P150. J. Biol. Chem. 264, 4648–4656 (1989).
Herzog, W. & Weber, K. Fractionation of brain microtubule-associated proteins. Isolation of two different proteins which stimulate tubulin polymerization in vitro. Eur. J. Biochem. 92, 1–8 (1978).
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
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.
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1038/nrm1527
This article is cited by
-
Synaptic retrograde regulation of the PKA-induced SNAP-25 and Synapsin-1 phosphorylation
Cellular & Molecular Biology Letters (2023)
-
Synaptic Mechanisms of Delay Eyeblink Classical Conditioning: AMPAR Trafficking and Gene Regulation in an In Vitro Model
Molecular Neurobiology (2023)
-
AKAP13 Enhances CREB1 Activation by FSH in Granulosa Cells
Reproductive Sciences (2023)
-
High AKAP8L expression predicts poor prognosis in esophageal squamous cell carcinoma
Cancer Cell International (2022)
-
A multiscale model of the regulation of aquaporin 2 recycling
npj Systems Biology and Applications (2022)