AKAP5

Summary

AKAP5 (A-kinase anchoring protein 5, HGNC:375) is a protein-coding gene on chromosome 14q23.3, encoding A-kinase anchor protein 5 (P24588). Multivalent scaffold protein that anchors the cAMP-dependent protein kinase/PKA to cytoskeletal and/or organelle-associated proteins, targeting the signal carried by cAMP to specific intracellular effectors.

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein binds to the RII-beta regulatory subunit of PKA, and also to protein kinase C and the phosphatase calcineurin. It is predominantly expressed in cerebral cortex and may anchor the PKA protein at postsynaptic densities (PSD) and be involved in the regulation of postsynaptic events. It is also expressed in T lymphocytes and may function to inhibit interleukin-2 transcription by disrupting calcineurin-dependent dephosphorylation of NFAT.

Source: NCBI Gene 9495 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 67 total — 1 pathogenic
• MANE Select transcript: NM_004857

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:375
Approved symbol	AKAP5
Name	A-kinase anchoring protein 5
Location	14q23.3
Locus type	gene with protein product
Status	Approved
Aliases	AKAP75, AKAP79
Ensembl gene	ENSG00000179841
Ensembl biotype	protein_coding
OMIM	604688
Entrez	9495

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000320636, ENST00000394718

RefSeq mRNA: 1 — MANE Select: NM_004857 NM_004857

CCDS: CCDS9764

Canonical transcript exons

ENST00000394718 — 2 exons

Exon	Start	End
ENSE00001519350	64468132	64474503
ENSE00001631134	64465499	64465613

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 91.67.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7164 / max 172.2434, expressed in 604 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140103	1.4128	347
140102	0.5122	194
140098	0.2889	81
140101	0.2236	89
140100	0.1709	77
140099	0.1080	41

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	91.67	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.41	gold quality
entorhinal cortex	UBERON:0002728	87.31	gold quality
superior frontal gyrus	UBERON:0002661	85.61	gold quality
postcentral gyrus	UBERON:0002581	85.59	gold quality
nucleus accumbens	UBERON:0001882	85.26	gold quality
parietal lobe	UBERON:0001872	82.82	gold quality
primary visual cortex	UBERON:0002436	81.49	gold quality
endothelial cell	CL:0000115	81.04	silver quality
caudate nucleus	UBERON:0001873	80.31	gold quality
prefrontal cortex	UBERON:0000451	79.96	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.01	gold quality
temporal lobe	UBERON:0001871	78.51	gold quality
putamen	UBERON:0001874	78.21	gold quality
telencephalon	UBERON:0001893	78.20	gold quality
frontal cortex	UBERON:0001870	78.19	gold quality
mucosa of sigmoid colon	UBERON:0004993	78.13	gold quality
occipital lobe	UBERON:0002021	77.81	gold quality
cerebral cortex	UBERON:0000956	77.62	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.39	gold quality
neocortex	UBERON:0001950	77.35	gold quality
colonic mucosa	UBERON:0000317	76.84	gold quality
cortical plate	UBERON:0005343	76.55	gold quality
forebrain	UBERON:0001890	75.07	gold quality
pigmented layer of retina	UBERON:0001782	74.68	gold quality
right frontal lobe	UBERON:0002810	74.66	gold quality
Ammon’s horn	UBERON:0001954	74.40	gold quality
cingulate cortex	UBERON:0003027	74.02	gold quality
amygdala	UBERON:0001876	73.81	gold quality
anterior cingulate cortex	UBERON:0009835	73.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.39
E-ENAD-27	no	3.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

210 targeting AKAP5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-373-5P	99.98	75.36	4753

Literature-anchored findings (GeneRIF, showing 40)

• that during prenatal development AKAP79 expression increased gradually in the red nucleus (PMID:12077483)
• Trafficking of L-type calcium channels is mediated by the postsynaptic scaffolding protein AKAP79. (PMID:12114507)
• AKAP79 has a role in organizing large signalling complexes (PMID:12507994)
• Data suggest that cyclic AMP/protein kinase A may be coupled with calcium/calmodulin and guanosine triphosphatases through an IQGAP1/AKAP79 complex. (PMID:12938160)
• there is 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 (PMID:15671033)
• AKAP79 provides cyclic AMP-dependent protein kinase to phosphorylate the beta1-adrenergic receptor and thereby dictate the recycling and resensitization itineraries of the beta1-adrenergic receptor (PMID:16940053)
• AKAP79 interacts with adenylyl cyclase V and adenylyl cyclase VI in a complex that associates with protein kinase A forming a negative feedback loop that termporally regulates cAMP production. (PMID:16973443)
• AKAP150 and the protein phosphatase calcineurin are binding proteins to ASIC2a, and calcineurin regulates ASIC1a and ASIC2a activity (PMID:17548344)
• AKAP79 provides a mechanism to overcome limitations in kinase abundance thereby ensuring faithful signal propagation and efficient modification of AMPA receptor-mediated responses (PMID:18305116)
• AKAP5 protein is associated with its G-protein-coupled receptor, at the cell membrane, docked with the receptor during agonist-induced internalization and later receptor recycling after agonist wash-out. (PMID:18950703)
• Data reveal that an association of the Ca(2+)-stimulable AC8 with AKAP79/150 that limits the sensitivity of AC8 to intracellular Ca(2+) events. (PMID:20410303)
• Studies indicate that the cAMP signaling pathway is organized by A-kinase anchoring proteins and AKAP79 remainis the best-understood anchoring protein. (PMID:20883492)
• by favoring apoCaM binding to AKAP79, KN-62 and KN-93 derail the ability of AKAP79 to efficiently recruit PKC for regulation of GluA1. Thus, AKAP79 endows PKC with a pharmacological profile that overlaps with CaMKII. (PMID:21156788)
• AKAP79 may be the key AKAPs responsible for regulating antigen presentation. (PMID:21221125)
• dimeric AKAP79 concentrates pockets of second messenger responsive enzyme activities at the plasma membrane. (PMID:21464287)
• Mutation of the two critical cysteines results in exclusion of AKAP79 from lipid rafts and alterations in its membrane diffusion behavior and is accompanied by a loss of the ability of AKAP79 to regulate AC8. (PMID:21771783)
• show that an IAIIIT anchoring site in human AKAP79 binds the same surface of calcineurin as the PxIxIT recognition peptide of NFAT, albeit more strongly (PMID:22343722)
• results reveal novel roles for the AKAP79/150 signaling complex in dendritic endosomes. (PMID:22623657)
• AKAP79 directly interacts with Cav1.2 c-terminus and modulates Cav1.2 membrane targeting. (PMID:22677788)
• We demonstrate that calmodulin and caldendrin compete for a partially overlapping binding site on AKAP79 and that their binding is differentially dependent on calcium (PMID:22693956)
• the direct anchoring of both PKA and AC to TRPV1 by AKAP79/150 facilitates the response to inflammatory mediators and may be critical in the pathogenesis of thermal hyperalgesia. (PMID:23264624)
• AKAP5 Pro100Leu effects on emotion processing might be task-dependent with Pro homozygotes showing lower control of emotional interference, but more efficient processing of task-relevant emotional stimuli. (PMID:23383244)
• Patients with bipolar disorder have higher density of AKAP5-expressing neurons in the anterior cingulate cortex compared with controls. (PMID:23462372)
• Antagonizing the interaction between AKAP79 and TRPV1 inhibits inflammatory hyperalgesia. (PMID:23616546)
• The results of this study suggested that antagonizing the TRPV1-AKAP79 interaction will be a useful strategy for inhibiting inflammatory hyperalgesia. (PMID:23699529)
• AKAP79, PKC, PKA and PDE4 participate in a Gq-linked muscarinic receptor and adenylate cyclase 2 cAMP signalling complex. (PMID:23889134)
• a significant role for the AKAP5 scaffold in signaling and trafficking of the beta1-AR in cardiac myocytes and mammalian cells. (PMID:24121510)
• GPR30 interacted with membrane-associated guanylate kinases and protein kinase A-anchoring protein (AKAP) 5 in the plasma membrane in a PDZ-dependent manner. (PMID:24962572)
• Cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy. (PMID:25637608)
• human AKAP79-anchored PKC selectively phosphorylates the Robo3.1 receptor subtype on serine 1330 (PMID:25882844)
• Studies indicate the importance of the AKAP79/PP2B/protein kinase A complex’s role in synaptic long-term depression in the CA1 region of the hippocampus. (PMID:27911714)
• A short-linear interaction motif between residues 337-343 of AKAP79 is the sole PP2B-anchoring determinant sustaining these diverse topologies. (PMID:28967377)
• We determined a crystal structure of CaM bound to a peptide encompassing its binding site in AKAP79. CaM adopts a highly compact conformation in which its open Ca(2+)-activated C-lobe and closed N-lobe cooperate to recognize a mixed alpha/310 helix in AKAP79. (PMID:29162807)
• results provide the first direct evidence for a function of the well-described AKAP79/150 trafficking in regulating LTD-induced spine shrinkage. (PMID:29196604)
• These findings suggest that AKAP79, by orchestrating phosphorylation, represents a key to a GluA1 phosphorylation passcode, which allows the GluA1 subunit to escape GluA2 dominance and promote the appearance of CP-AMPARs. (PMID:30737285)
• AKAP79/150 LZ motif functions to recruit NFAT to the L-type calcium channels signaling complex to promote its activation by AKAP-anchored calcineurin. (PMID:31091162)
• AKAP5 anchors PKA to enhance regulation of the HERG channel. (PMID:32173522)
• AKAP5 complex facilitates purinergic modulation of vascular L-type Ca(2+) channel CaV1.2. (PMID:33082339)
• AKAP79/150 coordinates leptin-induced PKA signaling to regulate KATP channel trafficking in pancreatic beta-cells. (PMID:33617875)
• The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca(2+) entry. (PMID:33941685)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Akap5	ENSMUSG00000021057
rattus_norvegicus	Akap5	ENSRNOG00000006410

Protein

Protein identifiers

A-kinase anchor protein 5 — P24588 (reviewed: P24588)

Alternative names: A-kinase anchor protein 79 kDa, H21, cAMP-dependent protein kinase regulatory subunit II high affinity-binding protein

All UniProt accessions (1): P24588

UniProt curated annotations — full annotation on UniProt →

Function. Multivalent scaffold protein that anchors the cAMP-dependent protein kinase/PKA to cytoskeletal and/or organelle-associated proteins, targeting the signal carried by cAMP to specific intracellular effectors. Association with the beta2-adrenergic receptor (beta2-AR) not only regulates beta2-AR signaling pathway, but also the activation by PKA by switching off the beta2-AR signaling cascade. Plays a role in long term synaptic potentiation by regulating protein trafficking from the dendritic recycling endosomes to the plasma membrane and controlling both structural and functional plasticity at excitatory synapses. In hippocampal pyramidal neurons, recruits KCNK2/TREK-1 channel at postsynaptic dense bodies microdomains and converts it to a leak channel no longer sensitive to stimulation by arachidonic acid, acidic pH or mechanical stress, nor inhibited by Gq-coupled receptors but still under the negative control of Gs-coupled receptors. Associates with ORAI1 pore-forming subunit of CRAC channels in Ca(2+) signaling microdomains where it recruits NFATC2/NFAT1 and couples store-operated Ca(2+) influx to calmodulin and calcineurin signaling and activation of NFAT-dependent transcriptional responses.

Subunit / interactions. Binding protein for dimer of the RII-beta regulatory subunit of cAMP-dependent protein kinase (PKA) and also for the protein kinase C (PKC) and the phosphatase calcineurin (PP2B). Each enzyme is inhibited when bound to the anchoring protein. Also binds the beta2-adrenergic receptor. Part of a complex containing AKAP5, ADCY5, ADCY6 and PDE4C. Interacts with ADCY8, and enhances its phosphorylation at lipid rafts. Interacts with ORAI1 (isoform alpha) (via N-terminus) upon store depletion and in response to LTC4. Does not interact with ORAI2 and ORAI3 paralogs. Interacts (via leucine zipper domain) with NFATC2/NFAT1. Interacts with calmodulin; the interaction is calcium-independent. Interacts with KCNQ2; the interaction may help KCNQ2 channel complex to retain calcium-bound calmodulin. Interacts with KCNK2; the channel is recruited to postsynaptic microdomains by AKAP5 where it can integrate neurotransmitter receptor signals. Part of a complex composed of AKAP5 and ADRB2.

Subcellular location. Postsynaptic recycling endosome membrane. Cell projection. Dendrite. Postsynaptic cell membrane.

Tissue specificity. Predominantly in the cerebral cortex and the postsynaptic densities of the forebrain, and to a lesser extent in adrenal medulla, lung and anterior pituitary.

Post-translational modifications. Palmitoylated. Palmitoylation at Cys-36 and Cys-129 play a key role in the targeting of AKAP5 to lipid rafts. Palmitoylation by ZDHHC2 is required for AKAP5 function in LTP-stimulated recycling endosome exocytosis.

Domain organisation. RII-alpha binding site, predicted to form an amphipathic helix, could participate in protein-protein interactions with a complementary surface on the R-subunit dimer. The N-terminal region, which is highly basic, is required for interaction with calmodulin.

RefSeq proteins (1): NP_004848* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001573	AKAP_WSK	Domain
IPR042375	AKAP5	Family

Pfam: PF03832

UniProt features (34 total): region of interest 7, mutagenesis site 7, compositionally biased region 6, sequence variant 3, lipid moiety-binding region 2, sequence conflict 2, helix 2, chain 1, modified residue 1, strand 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5NIN	X-RAY DIFFRACTION	1.7
3LL8	X-RAY DIFFRACTION	2
2H9R	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24588-F1	54.66	0.05

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 22, 36, 129

Mutagenesis-validated functional residues (7):

Position	Phenotype
36	loss of palmitoylation by zdhhc2; when associated with s-129.
129	loss of palmitoylation by zdhhc2; when associated with s-36.
392	prevents or diminishes rii binding.
396	prevents or diminishes rii binding.
400	prevents or diminishes rii binding.
405	prevents or diminishes rii binding.
408	prevents or diminishes rii binding.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-399719	Trafficking of AMPA receptors
R-HSA-9010642	ROBO receptors bind AKAP5
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-163685	Integration of energy metabolism
R-HSA-376176	Signaling by ROBO receptors
R-HSA-399721	Glutamate binding, activation of AMPA receptors and synaptic plasticity
R-HSA-422356	Regulation of insulin secretion
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 274 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_SYNAPSE_ASSEMBLY, FISCHER_G1_S_CELL_CYCLE, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, PID_NFAT_3PATHWAY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (12): signal transduction (GO:0007165), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), negative regulation of adenylate cyclase activity (GO:0007194), chemical synaptic transmission (GO:0007268), obsolete regulation of protein kinase A signaling (GO:0010738), calcineurin-NFAT signaling cascade (GO:0033173), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886), positive regulation of long-term synaptic potentiation (GO:1900273), positive regulation of protein localization to plasma membrane (GO:1903078), positive regulation of calcium ion import across plasma membrane (GO:1905665), positive regulation of endosome to plasma membrane protein transport (GO:1905751), positive regulation of adenylate cyclase activity (GO:0045762)

GO Molecular Function (12): calmodulin binding (GO:0005516), adenylate cyclase binding (GO:0008179), SH3 domain binding (GO:0017124), protein phosphatase 2B binding (GO:0030346), beta-2 adrenergic receptor binding (GO:0031698), protein kinase A regulatory subunit binding (GO:0034237), glutamate receptor binding (GO:0035254), GABA receptor binding (GO:0050811), protein kinase A binding (GO:0051018), molecular adaptor activity (GO:0060090), scaffold protein binding (GO:0097110), protein binding (GO:0005515)

GO Cellular Component (17): cytosol (GO:0005829), plasma membrane (GO:0005886), protein serine/threonine phosphatase complex (GO:0008287), cytoplasmic side of plasma membrane (GO:0009898), postsynaptic density (GO:0014069), dendrite (GO:0030425), dendrite membrane (GO:0032590), dendritic spine (GO:0043197), membrane raft (GO:0045121), postsynaptic membrane (GO:0045211), excitatory synapse (GO:0060076), postsynaptic recycling endosome (GO:0098837), postsynaptic recycling endosome membrane (GO:0098944), endosome (GO:0005768), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Regulation of insulin secretion	1
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1
Signaling by ROBO receptors	1
Transmission across Chemical Synapses	1
Neuronal System	1
Metabolism	1
Axon guidance	1
Neurotransmitter receptors and postsynaptic signal transmission	1
Integration of energy metabolism	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	3
postsynapse	3
adenylate cyclase activity	2
regulation of adenylate cyclase activity	2
signaling receptor binding	2
binding	2
dendrite	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
negative regulation of catalytic activity	1
anterograde trans-synaptic signaling	1
calcineurin-mediated signaling	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-NFAT signaling cascade	1
positive regulation of calcineurin-mediated signaling	1
positive regulation of synaptic transmission	1
long-term synaptic potentiation	1
regulation of long-term synaptic potentiation	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
positive regulation of protein localization to cell periphery	1
positive regulation of protein localization to membrane	1
positive regulation of calcium ion import	1
calcium ion import across plasma membrane	1
positive regulation of calcium ion transmembrane transport	1
regulation of calcium ion import across plasma membrane	1
positive regulation of intracellular protein transport	1
endosome to plasma membrane protein transport	1
positive regulation of protein localization to plasma membrane	1
regulation of endosome to plasma membrane protein transport	1
positive regulation of endocytic recycling	1
positive regulation of cyclase activity	1
positive regulation of lyase activity	1
enzyme binding	1

Protein interactions and networks

STRING

748 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKAP5	PRKACA	P17612	985
AKAP5	PRKACB	P22694	985
AKAP5	PRKACG	P22612	985
AKAP5	PRKAR2B	P31323	967
AKAP5	ADCY5	O95622	966
AKAP5	DLG1	Q12959	938
AKAP5	AKAP1	Q92667	931
AKAP5	DLG4	P78352	881
AKAP5	ADRB2	P07550	877
AKAP5	AKAP7	O43687	848
AKAP5	AKAP12	Q02952	845
AKAP5	CALM1	P02593	843
AKAP5	AKAP8	O43823	842
AKAP5	CACNA1C	Q13936	839
AKAP5	ADCY6	O43306	826

IntAct

58 interactions, top by confidence:

A	B	Type	Score
PRKAR2B	AKAP5	psi-mi:“MI:0915”(physical association)	0.800
AKAP5	PRKAR2B	psi-mi:“MI:0915”(physical association)	0.800
PRKACB	PRKAR1A	psi-mi:“MI:0914”(association)	0.790
AKAP5	PRKAR2A	psi-mi:“MI:0915”(physical association)	0.760
AKAP5	PRKAR2A	psi-mi:“MI:2364”(proximity)	0.760
AKAP5	PRKAR2A	psi-mi:“MI:0407”(direct interaction)	0.760
PRKACA	VAPB	psi-mi:“MI:0914”(association)	0.730
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
PPP3CA	AKAP5	psi-mi:“MI:0915”(physical association)	0.650
PPP3CA	AKAP5	psi-mi:“MI:2364”(proximity)	0.650
AKAP5	PPP3R1	psi-mi:“MI:0915”(physical association)	0.590
GPER1	ADRB1	psi-mi:“MI:0914”(association)	0.570
AKAP5	ROPN1L	psi-mi:“MI:0915”(physical association)	0.560
AKAP5	PPP3CA	psi-mi:“MI:0915”(physical association)	0.560
PRKAR1A	AKAP5	psi-mi:“MI:0915”(physical association)	0.560
AKAP5	ROPN1	psi-mi:“MI:0915”(physical association)	0.560
PRKACB	PRKAR1A	psi-mi:“MI:0914”(association)	0.550
AKAP5	KCNJ2	psi-mi:“MI:0915”(physical association)	0.540
PRKACG	UBB	psi-mi:“MI:0914”(association)	0.530
PRKAR2B	AMY1A	psi-mi:“MI:0914”(association)	0.530
PRKACB	VAPB	psi-mi:“MI:0914”(association)	0.530
Kcnj2	AKAP5	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (117): AKAP5 (Affinity Capture-MS), AKAP5 (Proximity Label-MS), CLK1 (Affinity Capture-MS), HSPA2 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), TNPO1 (Affinity Capture-MS), NCL (Affinity Capture-MS), PRKACA (Affinity Capture-MS), PRKACB (Affinity Capture-MS), PRKAR2A (Affinity Capture-MS), SUV39H1 (Affinity Capture-MS), HIST1H3A (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), PRPF4B (Affinity Capture-MS), OTUD6B (Affinity Capture-MS)

ESM2 similar proteins: A2A995, A2ALU4, A4IGN8, A6NMK8, D3ZUI5, E1C2Q8, F1QGH6, O54931, O75128, O75363, O75410, O95425, P24275, P24588, P51827, Q1LWM5, Q1RMS0, Q1W617, Q3UHI0, Q3UMF0, Q3ZB98, Q499V8, Q53SF7, Q5JR59, Q5NBX1, Q5VWT5, Q5ZJ26, Q62394, Q66KC9, Q673G8, Q69ZL1, Q6GQV1, Q6INC4, Q6QZN6, Q6WKZ4, Q6Y685, Q7TP36, Q7TS75, Q80YN3, Q8BI29

Diamond homologs: D3YVF0, P24275, P24587, P24588

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ZDHHC2	“up-regulates activity”	AKAP5	palmitoylation
AKAP5	“up-regulates activity”	PPP3CC	relocalization
AKAP5	“up-regulates activity”	PRKACA	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
DARPP-32 events	9	171.3×	1e-16
PKA activation in glucagon signalling	6	161.2×	1e-10
PKA activation	6	152.3×	1e-10
PKA-mediated phosphorylation of CREB	6	137.0×	2e-10
CD209 (DC-SIGN) signaling	5	103.8×	2e-08
Anti-inflammatory response favouring Leishmania parasite infection	6	94.5×	1e-09
Leishmania parasite growth and survival	6	94.5×	1e-09
Calmodulin induced events	6	91.4×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
vascular endothelial cell response to laminar fluid shear stress	6	137.4×	1e-09
renal water homeostasis	6	95.8×	4e-09
positive regulation of insulin secretion	5	39.9×	1e-05
adenylate cyclase-activating G protein-coupled receptor signaling pathway	9	31.8×	1e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

67 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	56
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
149197	GRCh38/hg38 14q23.2-23.3(chr14:62252700-65753416)x1	Pathogenic

SpliceAI

186 predictions. Top by Δscore:

Variant	Effect	Δscore
14:64465609:CCTAC:C	donor_gain	1.0000
14:64465610:CTAC:C	donor_gain	1.0000
14:64465611:TAC:T	donor_gain	1.0000
14:64465611:TACG:T	donor_loss	1.0000
14:64465612:AC:A	donor_gain	1.0000
14:64465614:G:GG	donor_gain	1.0000
14:64465615:T:TC	donor_loss	1.0000
14:64465618:G:GG	donor_gain	1.0000
14:64465617:A:AG	donor_gain	0.9800
14:64465613:CGT:C	donor_gain	0.9700
14:64465615:T:C	donor_gain	0.9700
14:64465614:G:C	donor_gain	0.9500
14:64465612:ACGT:A	donor_gain	0.9400
14:64465625:C:T	donor_gain	0.9100
14:64465610:CTACG:C	donor_gain	0.9000
14:64465611:TACGT:T	donor_gain	0.9000
14:64465616:A:AA	donor_gain	0.9000
14:64465616:A:AG	donor_loss	0.8700
14:64465607:GCCC:G	donor_gain	0.8000
14:64469921:G:GT	donor_gain	0.7800
14:64465615:TAA:T	donor_gain	0.7600
14:64466134:A:T	donor_gain	0.7200
14:64468126:CATCA:C	acceptor_loss	0.7000
14:64468127:ATCAG:A	acceptor_loss	0.7000
14:64468128:TCA:T	acceptor_loss	0.7000
14:64468129:CA:C	acceptor_loss	0.7000
14:64466070:C:A	donor_gain	0.6900
14:64466087:A:T	donor_gain	0.6800
14:64465610:C:G	donor_gain	0.6200
14:64466138:G:GT	donor_gain	0.6200

AlphaMissense

2822 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:64469581:C:A	A396D	0.996
14:64469601:G:C	A403P	0.996
14:64469569:T:C	L392S	0.994
14:64469590:T:C	L399P	0.994
14:64469593:T:A	V400D	0.994
14:64469580:G:C	A396P	0.993
14:64469626:T:C	L411P	0.991
14:64469590:T:A	L399Q	0.981
14:64468504:T:C	F37S	0.980
14:64469413:T:A	I340N	0.980
14:64469413:T:G	I340S	0.980
14:64469419:T:A	I342N	0.980
14:64469419:T:G	I342S	0.980
14:64469566:T:C	L391P	0.979
14:64469602:C:A	A403D	0.979
14:64469413:T:C	I340T	0.976
14:64469442:T:C	F350L	0.975
14:64469444:T:A	F350L	0.975
14:64469444:T:G	F350L	0.975
14:64469586:T:C	S398P	0.975
14:64469613:T:C	S407P	0.975
14:64469419:T:C	I342T	0.974
14:64469605:T:A	I404N	0.974
14:64469605:T:G	I404S	0.974
14:64468503:T:C	F37L	0.973
14:64468505:C:A	F37L	0.973
14:64468505:C:G	F37L	0.973
14:64469577:A:C	T395P	0.973
14:64469410:C:A	A339D	0.969
14:64468508:G:C	K38N	0.968

dbSNP variants (sampled 300 via entrez): RS1000036268 (14:64472171 A>T), RS1000507083 (14:64474792 T>A), RS1000765354 (14:64467431 T>C), RS1000826772 (14:64466614 A>T), RS1001107427 (14:64466233 T>A), RS1001114365 (14:64467042 A>G), RS1001166263 (14:64472026 G>A,C), RS1001933545 (14:64468114 T>C), RS1002176659 (14:64473779 T>A), RS1002282727 (14:64467638 C>T), RS1002565477 (14:64471326 G>A,C), RS1002772674 (14:64464043 T>G), RS1003126052 (14:64470416 C>G), RS1003128692 (14:64463748 G>A,C), RS1003500134 (14:64469627 G>A,C)

Disease associations

OMIM: gene MIM:604688 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Valproic Acid	decreases palmitoylation, increases expression	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
sotorasib	affects cotreatment, increases expression	1
lasiocarpine	increases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
tebuconazole	decreases expression	1
monomethylarsonous acid	decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Vehicle Emissions	decreases methylation	1
Cycloheximide	decreases expression, decreases reaction	1
Diethylhexyl Phthalate	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	increases expression	1
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	1
Aflatoxin B1	decreases methylation	1
Aflatoxin M1	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.