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Gene Review

AKAP5  -  A kinase (PRKA) anchor protein 5

Homo sapiens

Synonyms: A-kinase anchor protein 5, A-kinase anchor protein 79 kDa, AKAP 79, AKAP-5, AKAP75, ...
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Disease relevance of AKAP5

  • In vivo expression of exogenous AKAP75 in common carotid arteries, subjected to balloon injury, significantly increased the levels of p27(kip1) and inhibited neointimal hyperplasia [1].
  • Cholera toxin induces similar decreases in alpha s in wild type S49 lymphoma cells, in S49 kin- mutants, which lack cAMP-dependent protein kinase, and in S49 H21 a mutants, in which alpha s is unable to assume an active conformation upon binding GTP [2].
  • Hemoglobin Old Dominion/Burton-upon-Trent, beta 143 (H21) His-->Tyr, codon 143 CAC-->TAC--a variant with altered oxygen affinity that compromises measurement of glycated hemoglobin in diabetes mellitus: structure, function, and DNA sequence [3].

High impact information on AKAP5

  • Using this approach, we show that AKAP79/150 coordinates different enzyme combinations to modulate the activity of two distinct neuronal ion channels: AMPA-type glutamate receptors and M-type potassium channels [4].
  • We developed a new strategy that combines RNA interference of the endogenous protein with a protocol that selects cells that have been rescued with AKAP79/150 forms that are unable to anchor selected enzymes [4].
  • Cell-based studies indicate that phosphorylation of AMPA receptors is enhanced by a SAP97-AKAP79 complex that directs PKA to GluR1 via a PDZ domain interaction [5].
  • To investigate whether c-Myc is involved in tumor necrosis factor alpha (TNF-alpha)-mediated cell killing, we have examined two HeLa cell lines (D98 and H21) which show dramatic differences in their susceptibilities to TNF-alpha cytotoxicity [6].
  • Whereas several endogenous AKAPs were identified in HEK-293 cells, small interfering RNA-mediated down-regulation of AKAP79 prevented the recycling of the beta(1)-AR in this cell line [7].

Biological context of AKAP5

  • In AKAP79 immunopreparations, the magnocellular part became well demarcated from 23 weeks of gestation onwards and both parts showed punctate immunolabelling with moderate to high packing densities of immunoreactive cells [8].
  • Thus we propose a novel mechanism whereby AKAP79 and L-type VGCCs function as components of a biosynthetic mechanism that favors membrane incorporation of organized molecular complexes in a manner that is independent of PKA phosphorylation events [9].
  • This cDNA (2621 base pairs) encodes a protein of 427 amino acids with 76% identity to bovine brain AKAP 75 and 93% identity to a carboxyl-terminal RII-binding fragment of murine brain AKAP 150 [10].
  • Co-immunoprecipitations and fluorescence resonance energy transfer (FRET) microscopy experiments in HEK-293 cells revealed that the beta(1)-AR, AKAP79, and PKA form a ternary complex at the carboxyl terminus of the beta(1)-AR [7].
  • Mutagenesis, recombinant protein expression, and physicochemical characterization were used to investigate the structural basis for the homodimerization and AKAP75 binding activities of RII beta [11].

Anatomical context of AKAP5

  • It was found that during prenatal development both AKAP79 and SYN expression increased gradually although a major alteration in the distribution of the proteins within the two compartments of the red nucleus was not observed [8].
  • Characterization of distinct tethering and intracellular targeting domains in AKAP75, a protein that links cAMP-dependent protein kinase II beta to the cytoskeleton [12].
  • Immunological studies demonstrate that AKAP 79 is predominantly expressed in the cerebral cortex and is a component of fractions enriched for postsynaptic densities [10].
  • A highly acidic C-terminal region mediates the binding of RII beta (and cAMP-dependent protein kinase II beta), whereas a positively charged N-terminal segment contains structural features that are essential for the association of AKAP 75 with the cytoskeleton and/or intracellular membranes [13].
  • Antibodies against AKAP79 recognized a band at 86 kDa in purified plasma membranes from the PHM1-41 cells, indicating similar determinants in these proteins [14].

Associations of AKAP5 with chemical compounds

  • In support of this, glutathione S-transferase fusion proteins of both the intracellular N and C domains of Kir2.1 isolated AKAP79 from cell lysates, while glutathione S-transferase alone failed to interact with AKAP79 [15].
  • Selective siRNA-mediated knockdown identifies AKAP79, which is constitutively associated with the beta2-AR, rather than isoprenaline-recruited gravin, as being the functionally relevant AKAP in this process [16].
  • In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150 [5].
  • Mutants of AKAP79 that do not bind PKA or target to the beta2AR markedly inhibit phosphorylation of beta2AR/PKA-. We show that PKA directly phosphorylates GRK2 on serine 685 [17].
  • AKAP79-mediated Targeting of the Cyclic AMP-dependent Protein Kinase to the beta1-Adrenergic Receptor Promotes Recycling and Functional Resensitization of the Receptor [7].

Physical interactions of AKAP5

  • Identification of an IQGAP1/AKAP79 complex in beta-cells [18].
  • Certain conservative mutations that should not alter significantly the overall hydrophobicity or helicity of the tethering region (e.g. replacement of Leu with Ala) diminish the RII beta binding activity of AKAP75 [12].
  • Antibodies directed against a hemagglutinin epitope tag on Kir2.1 coimmunoprecipitated AKAP79, indicating that the two proteins exist together in a complex within intact cells [15].

Regulatory relationships of AKAP5

  • 1. Functionally, the presence of AKAP79 enhanced the response of Kir2.1 to elevated intracellular cAMP, suggesting a requirement for a pool of PKA anchored close to the channel [15].
  • Here we show that AKAP79 also regulates the ability of GRK2 to phosphorylate agonist-occupied receptors [17].

Other interactions of AKAP5

  • Residues containing long aliphatic side chains are essential for the high affinity binding of RII beta by AKAP75 [12].
  • Together, these findings suggest that AKAP79 associates directly with the Kir2.1 ion channel and may serve to anchor kinase enzymes in close proximity to key channel phosphorylation sites [15].
  • Using deletional and substitutional analyses, we have identified a 13-amino acid region within CN that is essential for the interaction with NFAT and with two other CN-binding proteins, AKAP79 and Cabin-1 [19].
  • In addition, multivalent binding proteins such as AKAP79 and AKAP250 have been characterized and appear to serve as platforms for the assembly of kinase/phosphatase signaling complexes [20].
  • Localization of the A kinase anchoring protein AKAP79 in the human hippocampus [21].
  • The multivalent neuronal scaffold A-kinase-anchoring protein 79 (AKAP79) is known to bind PKC and is linked to GluR1 by synapse-associated protein 97 (SAP97) [22].

Analytical, diagnostic and therapeutic context of AKAP5

  • In Western blots, we identified AKAP150, a rodent homologue of human AKAP79 that coimmunoprecipitates with PKA, PKC, and actin [23].
  • We show here, by combining extracellular epitope splicing into the channel pore-forming subunit and immunoassays with whole cell and single channel electrophysiological recordings, that AKAP79 directly regulates cell surface expression of L-type calcium channels independently of PKA [9].
  • Expression in cerebellar granule cells of RIIbeta and AKAP75 genes by microinjection of specific expression vectors, markedly stimulated cAMP-induced transcription of the lacZ gene driven by a cAMP-responsive element promoter [24].
  • In in situ hybridization experiments, p alpha H21 hybridized, under high stringency conditions, to the centromeric region of all the human, chimpanzee, gorilla and orangutan chromosomes [25].
  • Sequence analysis confirmed the alphoid nature of the whole p alpha H21 insert [25].


  1. Membrane-bound protein kinase A inhibits smooth muscle cell proliferation in vitro and in vivo by amplifying cAMP-protein kinase A signals. Indolfi, C., Stabile, E., Coppola, C., Gallo, A., Perrino, C., Allevato, G., Cavuto, L., Torella, D., Di Lorenzo, E., Troncone, G., Feliciello, A., Avvedimento, E., Chiariello, M. Circ. Res. (2001) [Pubmed]
  2. Cholera toxin induces cAMP-independent degradation of Gs. Chang, F.H., Bourne, H.R. J. Biol. Chem. (1989) [Pubmed]
  3. Hemoglobin Old Dominion/Burton-upon-Trent, beta 143 (H21) His-->Tyr, codon 143 CAC-->TAC--a variant with altered oxygen affinity that compromises measurement of glycated hemoglobin in diabetes mellitus: structure, function, and DNA sequence. Elder, G.E., Lappin, T.R., Horne, A.B., Fairbanks, V.F., Jones, R.T., Winter, P.C., Green, B.N., Hoyer, J.D., Reynolds, T.M., Shih, D.T., McCormick, D.J., Kubik, K.S., Madden, B.J., Head, C.G., Harvey, D., Roberts, N.B. Mayo Clin. Proc. (1998) [Pubmed]
  4. Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. Hoshi, N., Langeberg, L.K., Scott, J.D. Nat. Cell Biol. (2005) [Pubmed]
  5. Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex. Colledge, M., Dean, R.A., Scott, G.K., Langeberg, L.K., Huganir, R.L., Scott, J.D. Neuron (2000) [Pubmed]
  6. Nuclear c-Myc plays an important role in the cytotoxicity of tumor necrosis factor alpha in tumor cells. Jänicke, R.U., Lee, F.H., Porter, A.G. Mol. Cell. Biol. (1994) [Pubmed]
  7. AKAP79-mediated Targeting of the Cyclic AMP-dependent Protein Kinase to the beta1-Adrenergic Receptor Promotes Recycling and Functional Resensitization of the Receptor. Gardner, L.A., Tavalin, S.J., Goehring, A.S., Scott, J.D., Bahouth, S.W. J. Biol. Chem. (2006) [Pubmed]
  8. Expression of a kinase anchoring protein 79 and synaptophysin in the developing human red nucleus. Ulfig, N., Chan, W.Y. Neurosignals (2002) [Pubmed]
  9. Trafficking of L-type calcium channels mediated by the postsynaptic scaffolding protein AKAP79. Altier, C., Dubel, S.J., Barrère, C., Jarvis, S.E., Stotz, S.C., Spaetgens, R.L., Scott, J.D., Cornet, V., De Waard, M., Zamponi, G.W., Nargeot, J., Bourinet, E. J. Biol. Chem. (2002) [Pubmed]
  10. Localization of the cAMP-dependent protein kinase to the postsynaptic densities by A-kinase anchoring proteins. Characterization of AKAP 79. Carr, D.W., Stofko-Hahn, R.E., Fraser, I.D., Cone, R.D., Scott, J.D. J. Biol. Chem. (1992) [Pubmed]
  11. Mutagenesis of the regulatory subunit (RII beta) of cAMP-dependent protein kinase II beta reveals hydrophobic amino acids that are essential for RII beta dimerization and/or anchoring RII beta to the cytoskeleton. Li, Y., Rubin, C.S. J. Biol. Chem. (1995) [Pubmed]
  12. Characterization of distinct tethering and intracellular targeting domains in AKAP75, a protein that links cAMP-dependent protein kinase II beta to the cytoskeleton. Glantz, S.B., Li, Y., Rubin, C.S. J. Biol. Chem. (1993) [Pubmed]
  13. Cloning and expression of an intron-less gene for AKAP 75, an anchor protein for the regulatory subunit of cAMP-dependent protein kinase II beta. Hirsch, A.H., Glantz, S.B., Li, Y., You, Y., Rubin, C.S. J. Biol. Chem. (1992) [Pubmed]
  14. Protein kinase A anchoring to the myometrial plasma membrane is required for cyclic adenosine 3',5'-monophosphate regulation of phosphatidylinositide turnover. Dodge, K.L., Carr, D.W., Sanborn, B.M. Endocrinology (1999) [Pubmed]
  15. Targeting of an A kinase-anchoring protein, AKAP79, to an inwardly rectifying potassium channel, Kir2.1. Dart, C., Leyland, M.L. J. Biol. Chem. (2001) [Pubmed]
  16. RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. Lynch, M.J., Baillie, G.S., Mohamed, A., Li, X., Maisonneuve, C., Klussmann, E., van Heeke, G., Houslay, M.D. J. Biol. Chem. (2005) [Pubmed]
  17. Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79. Cong, M., Perry, S.J., Lin, F.T., Fraser, I.D., Hu, L.A., Chen, W., Pitcher, J.A., Scott, J.D., Lefkowitz, R.J. J. Biol. Chem. (2001) [Pubmed]
  18. Identification of an IQGAP1/AKAP79 complex in beta-cells. Nauert, J.B., Rigas, J.D., Lester, L.B. J. Cell. Biochem. (2003) [Pubmed]
  19. The linker region joining the catalytic and the regulatory domains of CnA is essential for binding to NFAT. Rodríguez, A., Martínez-Martínez, S., López-Maderuelo, M.D., Ortega-Pérez, I., Redondo, J.M. J. Biol. Chem. (2005) [Pubmed]
  20. Anchoring and scaffold proteins for kinases and phosphatases. Lester, L.B., Scott, J.D. Recent Prog. Horm. Res. (1997) [Pubmed]
  21. Localization of the A kinase anchoring protein AKAP79 in the human hippocampus. Sík, A., Gulácsi, A., Lai, Y., Doyle, W.K., Pacia, S., Mody, I., Freund, T.F. Eur. J. Neurosci. (2000) [Pubmed]
  22. AKAP79 selectively enhances protein kinase C regulation of GluR1 at a Ca2+-calmodulin-dependent protein kinase II/protein kinase C site. Tavalin, S.J. J. Biol. Chem. (2008) [Pubmed]
  23. Association of protein kinase A with AKAP150 facilitates pepsinogen secretion from gastric chief cells. Xie, G., Raufman, J.P. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  24. The type and the localization of cAMP-dependent protein kinase regulate transmission of cAMP signals to the nucleus in cortical and cerebellar granule cells. Paolillo, M., Feliciello, A., Porcellini, A., Garbi, C., Bifulco, M., Schinelli, S., Ventra, C., Stabile, E., Ricciardelli, G., Schettini, G., Avvedimento, E.V. J. Biol. Chem. (1999) [Pubmed]
  25. An alphoid DNA sequence conserved in all human and great ape chromosomes: evidence for ancient centromeric sequences at human chromosomal regions 2q21 and 9q13. Baldini, A., Ried, T., Shridhar, V., Ogura, K., D'Aiuto, L., Rocchi, M., Ward, D.C. Hum. Genet. (1993) [Pubmed]
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