Association of an A-Kinase-anchoring Protein Signaling Scaffold with Cadherin Adhesion Molecules in Neurons and Epithelial Cells
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A-kinase-anchoring protein (AKAP) 79/150 organizes a scaffold of cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and protein phosphatase 2B/calcineurin that regulates phosphorylation pathways underlying neuronal long-term potentiation and long-term depression (LTD) synaptic plasticity. AKAP79/150 postsynaptic targeting requires three N-terminal basic domains that bind F-actin and acidic phospholipids. Here, we report a novel interaction of these domains with cadherin adhesion molecules that are linked to actin through beta-catenin (beta-cat) at neuronal synapses and epithelial adherens junctions. Mapping the AKAP binding site in cadherins identified overlap with beta-cat binding; however, no competition between AKAP and beta-cat binding to cadherins was detected in vitro. Accordingly, AKAP79/150 exhibited polarized localization with beta-cat and cadherins in epithelial cell lateral membranes, and beta-cat was present in AKAP-cadherin complexes isolated from epithelial cells, cultured neurons, and rat brain synaptic membranes. Inhibition of epithelial cell cadherin adhesion and actin polymerization redistributed intact AKAP-cadherin complexes from lateral membranes to intracellular compartments. In contrast, stimulation of neuronal pathways implicated in LTD that depolymerize postsynaptic F-actin disrupted AKAP-cadherin interactions and resulted in loss of the AKAP, but not cadherins, from synapses. This neuronal regulation of AKAP79/150 targeting to cadherins may be important in functional and structural synaptic modifications underlying plasticity.
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LTD leads to loss of AKAP79/150 binding to PSD-95 and cadherins and removal of the AKAP and PKA from synapses.
“LTD leads to loss of AKAP79/150 binding to PSD-95 and cadherins and removal of the AKAP and PKA from synapses”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Gorski et al., 2005
AKAP79/150 is targeted to dendritic spines and the PSD by an N-terminal basic region that is palmitoylated on two Cys residues and binds directly to PIP2, the actin cytoskeleton, and cadherin adhesion molecules.
“AKAP79/150 is targeted to dendritic spines and the PSD by an N-terminal basic region that is palmitoylated on two Cys residues and binds directly to the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2), the actin cytoskeleton, and cadherin adhesion molecules”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Gorski et al., 2005
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“However, NMDA as well as low-frequency LTD electrical stimulation cause loss of spine F-actin, leading to thin filopodial spines that should favor decreased adhesion (Halpain et al., 1998; Zhou et al., 2004).”
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Self-citationActivity-Regulated N-Cadherin Endocytosis
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BackgroundCell adhesion molecules at the synapse
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“It has been shown that AKAP organizes a scaffold of cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and protein phosphatase 2B/calcineurin, that regulates phosphorylation pathways underlying neuronal LTP and LTD (165).”
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“Associations with the actin cytoskeleton, acidic phospholipids, and cadherins target AKAP79/150 to the postsynaptic membrane (Dell'Acqua et al., 1998; Gomez et al., 2002; Gorski et al., 2005).”
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“…is palmitoylated on two Cys residues and binds directly to the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2), the actin cytoskeleton, and cadherin adhesion molecules (Dell’Acqua et al., 1998; Gomez et al., 2002; Gorski et al., 2005; Horne and Dell’Acqua, 2007; Keith et al., 2012).”
BackgroundMethodInfluentialSelf-citationA-kinase anchoring protein mediates TRPV1 thermal hyperalgesia through PKA phosphorylation of TRPV1
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Self-citationCoordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity
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“AKAP79/150 also acts as a structural scaffolding hub as it binds F-actin (20), the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate (21), synaptic adhesion molecules (22), and PSD-95 family scaffold proteins that link to NMDARs and AMPARs (23).”
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“AKAP79/150 spine localization requires an N-terminal targeting domain that binds phosphatidylinositol-(4,5)-bisphosphate (PIP2), F-actin, and cadherin adhesion molecules (Dell’Acqua et al., 1998; Gomez et al., 2002; Gorski et al., 2005).”
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“AKAP79/ 150 is targeted to dendritic spines by an N-terminal basic domain that binds the acidic phospholipid phosphatidylinositol-4,5bisphosphate (PI4,5P2), F-actin, and cadherin adhesion molecules (Dell’Acqua et al., 1998; Gomez et al., 2002; Gorski et al., 2005; Horne and Dell’Acqua, 2007).”
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“AKAP79/150 can also bind N-cadherin (a transsynaptic cell adhesion molecule) and the actin cytoskeleton (F-actin) via these domains (Dell’Acqua et al., 2002; Gomez et al., 2002; Gorski et al., 2005).”
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Cross-talk between calcium and protein kinase A in the regulation of cell migration
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“Another postsynaptic factor known as A-kinase-anchoring protein 79/150 (AKAP 79/150), which also associates with the b-catenin binding site of N-cadherin (Gorski et al., 2005), plays a critical role in the endocytosis of AMPA receptors (Bhattacharyya et al.”
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“In addition, AKAP12 regulates E-cadherin expression in prostate epithelial cells (1), and AKAP5 interacts with cadherins (10).”
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“2007) or affecting binding sites for other AKAP150-associated molecules including F-actin, cadherin, calmodulin, PKC, phosphatidylinositol-4,5-bisphosphate, and calcineurin (Gomez et al. 2002; Gorski et al. 2005).”
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“Overall, these results demonstrate a novel structural role for AKAP79/150 in which the N-terminal targeting domain induces dendritic filopodia and binding to MAGUKs promotes spine enlargement and AMPAR recruitment.”
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“AKAP79/150 is targeted to the postsynaptic plasma membrane primarily by an N-terminal poly-basic domain that binds to PIP2, cortical F-actin, and cadherin adhesion molecules and secondarily by an internal domain that binds PSD-95, a major structural scaffold of the PSD (Colledge et al., 2000; Dell’Acqua et al., 1998;…”
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“, 2002), cell adhesion molecules (Gorski et al., 2005), and other postsynaptic scaffold proteins (Colledge et al.”
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“Te-thering of AKAP5 to PSD is achieved via interaction of structural components including PIP2, F-actin, cadherins (Gomez et al., 2002; Gorski et al., 2005) and membrane-associated guanylate kinase (MAGUK) (Colledge et al., 2000; Robertson et al., 2009).”
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Cadherin-Based Transsynaptic Networks in Establishing and Modifying Neural Connectivity
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“…among the known neuronal PP1 regulators that are also postsynaptically localized, are Yotiao (Lin et al. 1998), NFL (Terry-Lorenzo et al. 2000) and AKAP79 (Gorski et al. 2005), and two neurabin isoforms, NrbI (Terry-Lorenzo et al. 2000) and NrbII (Satoh et al. 1998; Terry-Lorenzo et al. 2000).”
BackgroundRole of AKAP79/150 Protein in β1-Adrenergic Receptor Trafficking and Signaling in Mammalian Cells*
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“Loss of the calcineurin-binding site from AKAP5 affected the optimal positioning of MAGUK-AKAP5glutamate receptor complexes in the hippocampus and interfered with the phosphorylation and trafficking of -amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors (38, 39).”
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A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density
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“AKAPs (Akinase anchoring proteins) are also important interacting proteins for PKC signaling (6), able for instance to associate with cadherin adhesion molecules (16).”
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“2003), and binds to N-cadherin directly (Gorski et al., 2005), suggesting a further role in anchoring synaptic N-cadherin during LTP.”
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“AKAP79 was also shown to associate with PKC and to organize a scaffold with PKA and protein phosphatases (37).”
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“A-kinase anchoring proteins (AKAP) have also been linked to maintaining cAMP compartmentalization, which is associated with learning and memory [62], and have been shown to interact with cadherin adhesion molecules at the postsynaptic density, which is important for synaptic plasticity [63].”
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Lee, H., Yu, D.-M., Park, J. S., Lee, H., Kim, J.-S., Kim, H., Koo, S.-H., Lee, J.-S., Lee, S., & Ko, Y.-G. (2019) · bioRxiv · doi:10.15252/embr.201949416 · Cited by 15
“…phosphorylation of nuclear CREB is increased by its overexpression but is reduced by its knockdown (Fraser et al , 2000; Altier et al , 2002; Gorski et al , 2005). cAMP-induced phosphorylation of nuclear CREB is also reduced with a cell-permeable peptide treatment that inhibits the…”
AKAP79/150 interacts with the neuronal calcium‐binding protein caldendrin
Gorny, X., Mikhaylova, M., Seeger, C., Reddy, P. P., Reißner, C., Schott, B. H., Danielson, U. H., Kreutz, M. R., & Seidenbecher, C. I. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07828.x · Cited by 17 · see citing works
Chen, X., Crosby, K. C., Feng, A. Y., Purkey, A., Aronova, M. A., Winters, C. A., Crocker, V. T., Leapman, R. D., Reese, T. S., & Dell’Acqua, M. L. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.1004154 · Cited by 14 · see citing works
Self-citation“Shaping” of cell signaling via AKAP-tethered PDE4D: Probing with AKAR2-AKAP5 biosensor
Kocer, S. S., Wang, H.-Y., & Malbon, C. (2012) · Journal of Molecular Signaling · doi:10.1186/1750-2187-7-4 · Cited by 11 · see citing works
“In resting cells, absent any stimulation with β-adrenergic agonist, AKAR2-AKAP5 localizes to the cell membrane [22-25].”
The contribution of AKAP5 in amylase secretion from mouse parotid acini
Wu, C., DiJulio, D. H., Jacobson, K. L., McKnight, G. S., & Watson, E. L. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00382.2009 · Cited by 13 · see citing works
DrFLINC Contextualizes Super-resolution Activity Imaging
Lin, W., Mo, G., Mehta, S., & Zhang, J. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c05530 · Cited by 10
Wu, S., Shen, D., & Zhao, L. (2022) · Cancer Management and Research · doi:10.2147/cmar.s343033 · Cited by 13 · see citing works
Bogoch, Y., & Linial, M. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.12.003 · Cited by 9
“AKAP8 serves as a linker between PKA, PKC, Cadherin2, actin, MFs, β-catenin [32] and is also known to bind Figtl1 [33].”
BackgroundZhong, Z.-S., Ye, Z.-H., He, G., Zhang, W., Wang, J., & Huang, S.-P. (2020) · Annals of Translational Medicine · doi:10.21037/atm.2019.12.98 · Cited by 8 · see citing works
“AKAP5 can bind to E-cadherin and β-catenin to regulate mucosal adhesion junctions, which may be associated with tumor migration and metastasis (20).”
BackgroundHow anchoring proteins shape pain
Fischer, M. J. M., & McNaughton, P. A. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.04.001 · Cited by 9 · see citing works
“synaptic modifications underlying plasticity (Gorski et al., 2005), especially as AKAP79 is upregulated during long term potentiation (Génin et al.”
BackgroundGibson, E. S., Woolfrey, K. M., Li, H.-M., Hogan, P., Nemenoff, R., Heasley, L., & Dell'Acqua, M. (2018) · Molecular Pharmacology · doi:10.1124/mol.118.113159 · Cited by 5 · see citing works
“For measurements of FRET as CFP-donor dequenching after YFP-acceptor photobleaching (PB), YFPwas bleached in a subset of the same cells with 5356 20 nm light for 2minutes andCFP imaged again essentially as described previously (Oliveria et al., 2003, 2007; Gorski et al., 2005).”
MethodSelf-citationChu, C.-C., Hu, Y.-H., Li, G.-Z., Chen, J., Zhang, N.-N., Gu, Y., Wu, S., Zhang, H., Xu, Y.-Y., Guo, H.-L., et al. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106812 · Cited by 4 · see citing works
“…including F-actin (Gomez et al., 2002), PIP2 (Dell ’ Acqua et al., 1998b), MAGUKs (Robertson et al., 2009), cadherin cell adhesion molecule (Gorski et al., 2005), adenylyl cyclases (ACs) (Dessauer, 2009; Efendiev et al., 2010; Zhang et al., 2013), protein kinases (Hoshi et al., 2010), and…”
Postsynaptic Targeting of Protein Kinases and Phosphatases
Strack, S., & Hell, J. W. (2008) · Springer eBooks · doi:10.1007/978-0-387-77232-5_16 · Cited by 3 · see citing works
Cadherin-Mediated Adhesion and Signaling During Vertebrate Central Synapse Formation
Anderson, T. R., & Benson, D. (2006) · doi:10.1007/978-0-387-32562-0_6 · Cited by 2
Subcellular Targeting of PKA through AKAPs
Pink, M. D., & Dell’Acqua, M. L. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00165-0
Self-citationNanoscale Architecture Can Control Cellular Function.
Lee, H. N., Qiao, L., Zhong, Y.-H., Mehta, S., Nishida, A., Rangamani, P., & Zhang, J. (2026) · ACS Nano · doi:10.1021/acsnano.6c03529
Anchored kinase and phosphatase signaling networks in amyloid β-induced synaptic dysfunction
Koek, L. A., Jo, H.-N., Kennedy, M. J., & Dell’Acqua, M. L. (2026) · Molecular Pharmacology · doi:10.1016/j.molpha.2026.100141
Self-citationParra, L. G., Casali, C. I., Sendyk, D. E., Salafia, A. F., Flor, S. A., Lucangioli, S. E., & Tome, M. C. F. (2026) · Cell Stress · doi:10.15698/cst2026.04.317
“AKAP proteins, usually bound to the cytosolic domain of cadherins, attach to the regulatory subunits of PKA and drive its compartmentalization linking PKA to the classical cadherins VE-cadherin and E-cadherin [42,43].”
Globa, A. (2017) · doi:10.14288/1.0357129
“Interestingly, the mRNA transcript encoding the GluA2 subunit undergoes RNA editing which introduces a glutamine to arginine point mutation at the pore of the receptor.”
BackgroundInfluentialRole of AKAP5 in postsynaptic signaling complexes
Zhang, M. (2010) · doi:10.17077/etd.0caphnb1
“, 1992), PKC (Dell'Acqua et al., 1998; Gomez et al., 2002; Gorski et al., 2005; Klauck et al., 1996; Tavalin, 2008), and PP2B (Coghlan et al.”
Background
- Authors
- Gorski, J. A., Gomez, L. L., Scott, J. D., & Dell'Acqua, M. L.
- Affiliations
- University of Colorado Denver (US)
- Howard Hughes Medical Institute (US)
- Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045
- ORCID
- Scott, John D.
- Venue
- Molecular Biology of the Cell
- Published
- 2005-08
- Volume
- 16
- Issue
- 8
- Pages
- 3574-3590
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC1182299
- OpenAlex
- W2113913008
- Cited by
- 82
- References
- 53
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 8 · 2013: 2 · 2012: 7
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institute of General Medical Sciences (R01GM048231, GM-48231, R37GM048231)
- National Institute of Neurological Disorders and Stroke (R56NS040701, R01NS040701, NS-40701)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- AKAP79/150, protein kinase A, protein kinase C, calcineurin, cadherins, β-catenin, F-actin binding, synaptic plasticity, long-term depression, long-term potentiation, adherens junctions, actin depolymerization, protein phosphorylation, synaptic targeting, epithelial cells, neurons
- MeSH terms
- Actins, Animals, Binding Sites, Cell Adhesion, Cells, Cultured, Dogs, Epithelial Cells, Humans, Neurons, Protein Binding, Signal Transduction, Cadherins, Receptors, N-Methyl-D-Aspartate, Cell Polarity, Calcineurin, Fluorescence Resonance Energy Transfer, Adaptor Proteins, Signal Transducing, Rats, A Kinase Anchor Proteins
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