PRKAR2B

Summary

PRKAR2B (protein kinase cAMP-dependent type II regulatory subunit beta, HGNC:9392) is a protein-coding gene on chromosome 7q22.3, encoding cAMP-dependent protein kinase type II-beta regulatory subunit (P31323). Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.

cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. The protein encoded by this gene is one of the regulatory subunits. This subunit can be phosphorylated by the activated catalytic subunit. This subunit has been shown to interact with and suppress the transcriptional activity of the cAMP responsive element binding protein 1 (CREB1) in activated T cells. Knockout studies in mice suggest that this subunit may play an important role in regulating energy balance and adiposity. The studies also suggest that this subunit may mediate the gene induction and cataleptic behavior induced by haloperidol.

Source: NCBI Gene 5577 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 37 total
• Druggable target: yes
• MANE Select transcript: NM_002736

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9392
Approved symbol	PRKAR2B
Name	protein kinase cAMP-dependent type II regulatory subunit beta
Location	7q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000005249
Ensembl biotype	protein_coding
OMIM	176912
Entrez	5577

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 9 protein_coding_CDS_not_defined, 8 protein_coding, 6 retained_intron

ENST00000265717, ENST00000393613, ENST00000488792, ENST00000706580, ENST00000706581, ENST00000706582, ENST00000706583, ENST00000706584, ENST00000706585, ENST00000706586, ENST00000706587, ENST00000706588, ENST00000706589, ENST00000706590, ENST00000706591, ENST00000706592, ENST00000706593, ENST00000854597, ENST00000854598, ENST00000913925, ENST00000913926, ENST00000913927, ENST00000965652

RefSeq mRNA: 1 — MANE Select: NM_002736 NM_002736

CCDS: CCDS5740

Canonical transcript exons

ENST00000265717 — 11 exons

Exon	Start	End
ENSE00000715091	107146308	107146461
ENSE00000715093	107150922	107151023
ENSE00000715095	107153177	107153251
ENSE00000715098	107156984	107157049
ENSE00000715102	107157186	107157324
ENSE00000881748	107044705	107045214
ENSE00001174070	107159449	107161811
ENSE00003485946	107070281	107070316
ENSE00003486939	107121952	107122004
ENSE00003531280	107140847	107140953
ENSE00003534352	107128212	107128295

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 98.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.1497 / max 851.9031, expressed in 1427 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80425	19.6745	1367
80424	2.3125	718
80423	0.5333	311
80426	0.5046	190
80429	0.0668	29
80428	0.0419	18
80432	0.0156	3
80431	0.0006	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.78	gold quality
adrenal tissue	UBERON:0018303	98.15	gold quality
monocyte	CL:0000576	98.02	gold quality
leukocyte	CL:0000738	97.19	gold quality
mucosa of stomach	UBERON:0001199	94.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.84	gold quality
adipose tissue	UBERON:0001013	94.68	gold quality
superior frontal gyrus	UBERON:0002661	94.62	gold quality
right adrenal gland cortex	UBERON:0035827	94.37	gold quality
omental fat pad	UBERON:0010414	94.33	gold quality
left adrenal gland cortex	UBERON:0035825	93.74	gold quality
left adrenal gland	UBERON:0001234	93.66	gold quality
adrenal gland	UBERON:0002369	93.60	gold quality
right adrenal gland	UBERON:0001233	93.51	gold quality
embryo	UBERON:0000922	93.05	gold quality
ganglionic eminence	UBERON:0004023	93.05	gold quality
primary visual cortex	UBERON:0002436	92.81	gold quality
prefrontal cortex	UBERON:0000451	92.62	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.56	gold quality
lower esophagus	UBERON:0013473	92.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.48	gold quality
colonic epithelium	UBERON:0000397	92.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.12	gold quality
nucleus accumbens	UBERON:0001882	91.97	gold quality
caudate nucleus	UBERON:0001873	90.87	gold quality
frontal cortex	UBERON:0001870	90.79	gold quality
cerebral cortex	UBERON:0000956	90.66	gold quality
putamen	UBERON:0001874	90.57	gold quality
anterior cingulate cortex	UBERON:0009835	90.37	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	243.87
E-GEOD-76312	yes	125.79
E-MTAB-9067	yes	13.94
E-ANND-3	yes	6.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CEBPG, FOS, MYC, USF1, USF2

miRNA regulators (miRDB)

151 targeting PRKAR2B, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-1468-3P	99.96	72.74	3797

Literature-anchored findings (GeneRIF, showing 19)

• lipolytic catecholamine resistance of sc adipocytes in polycystic ovary syndrome is probably due to a combination of decreased amounts of beta(2)-adrenergic receptors, the regulatory II beta-component of protein kinase A, and hormone-sensitive lipase (PMID:12727985)
• Nuclear RII beta can act as a repressor of CREB transcriptional activity in T cells, providing a potential functional significance for aberrant levels of nuclear RII beta in systemic lupus erythematosus T cells. (PMID:14500661)
• there are abnormalities in [3H]cAMP binding and catalytic activity kinase A in brain of depressed suicide victims, which could be due to reduced expression of RIIbeta and Cbeta (PMID:14744463)
• serine 114 phosphorylation and nuclear localization of RIIbeta controls the regulation of IL-2 gene expression in T cells. (PMID:15187164)
• A high R1/R2 ratio favors the proliferation of well differentiated and hormone producing adrenocortical cells, while unbalanced expression of these subunits is not required for malignant transformation. (PMID:17904549)
• Loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. (PMID:18505904)
• PKA RII(beta) is responsible for increased glucocorticoid sensitivity, critical for cAMP-mediated synergistic cell killing in CEM cells (PMID:18544528)
• both the constitutive and cAMP-induced release of TNFR1 exosome-like vesicles occur via PKA-dependent pathways that are regulated by the anchoring of RIIbeta to BIG2 via AKAP domains B and C (PMID:18625701)
• Because of limited power, PRKAR2B’s role in antipsychotic-induced weight gain is unclear, but biological evidence suggests that PRKAR2B may be involved (PMID:24737441)
• Although the depletion of PRKAR1A and PRKAR2B in adrenocortical cells has similar effects on cell proliferation and apoptosis; loss of these PKA subunits differentially affects cyclin expression. (PMID:25268545)
• Leu206Arg and Leu199_Cys200insTrp mutations in PRKACA impair its association with PRKAR2B and PRKAR1A. (PMID:25477193)
• Release of pRIIbeta in the presence of cAMP is reduced by calcium, whereas autophosphorylation at the phosphorylation site inhibits holoenzyme reassociation with the catalytic subunit. (PMID:26158466)
• Study identified the overexpression of PRKAR2B in castration-resistant prostate cancer (CRPC) mouse models and patients, and showed it promoted CRPC cell proliferation, invasion and survival by mainly modulates cell cycle gene expression. These results provide evidence that PRKAR2B is a novel oncogenic gene in CRPC. (PMID:28008150)
• In this study, the authors linked for the first time the loss of RIIbeta protein levels to the PRKACA mutation status and found the down-regulation of RIIbeta to arise post-transcriptionally. (PMID:28250426)
• PRKAR2B induces epithelial-mesenchymal transition and promotes castration-resistant prostate cancers metastasis by activating the Wnt/beta-catenin signaling. PRKAR2B might be served as a potential target for castration-resistant prostate cancers therapy. (PMID:29761841)
• Biochemical studies demonstrate how the removal of ATP primes the holoenzyme for cAMP-mediated activation. The opposing competition between ATP/cAMP is unique to RIalpha..Comparisons to the RIIb holoenzyme demonstrate isoform-specific holoenzyme interfaces and highlights distinct allosteric mechanisms for activation in addition to the structural diversity of the isoforms (PMID:31363049)
• Transcriptional regulation of PRKAR2B by miR-200b-3p/200c-3p and XBP1 in human prostate cancer. (PMID:31986411)
• Hypoxia and the hypoxia inducible factor 1alpha activate protein kinase A by repressing RII beta subunit transcription. (PMID:32111982)
• PRKAR2B-HIF-1alpha loop promotes aerobic glycolysis and tumour growth in prostate cancer. (PMID:33025691)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	PRKAR2B	ENSDARG00000036446
mus_musculus	Prkar2b	ENSMUSG00000002997
rattus_norvegicus	Prkar2b	ENSRNOG00000009079

Paralogs (4): PRKAR1A (ENSG00000108946), PRKAR2A (ENSG00000114302), CNBD1 (ENSG00000176571), PRKAR1B (ENSG00000188191)

Protein

Protein identifiers

cAMP-dependent protein kinase type II-beta regulatory subunit — P31323 (reviewed: P31323)

All UniProt accessions (2): P31323, A0A9L9PXN2

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase.

Subunit / interactions. The inactive form of the enzyme is composed of two regulatory chains and two catalytic chains. Activation by cAMP produces two active catalytic monomers and a regulatory dimer that binds four cAMP molecules. Interacts with PRKACA and PRKACB. Interacts with the phosphorylated form of PJA2. Forms a complex composed of PRKAR2B, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Four types of regulatory chains are found: I-alpha, I-beta, II-alpha, and II-beta. Their expression varies among tissues and is in some cases constitutive and in others inducible.

Post-translational modifications. Phosphorylated by the activated catalytic chain.

Similarity. Belongs to the cAMP-dependent kinase regulatory chain family.

RefSeq proteins (1): NP_002727* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000595	cNMP-bd_dom	Domain
IPR003117	cAMP_dep_PK_reg_su_I/II_a/b	Domain
IPR012198	cAMP_dep_PK_reg_su	Family
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018488	cNMP-bd_CS	Conserved_site
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR050503	cAMP-dep_PK_reg_su-like	Family

Pfam: PF00027, PF02197

UniProt features (17 total): binding site 6, modified residue 4, region of interest 2, compositionally biased region 2, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31323-F1	79.37	0.42

Functional residue map

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

Ligand- & substrate-binding residues (6): 361; 154–275; 223; 232; 276–418; 352

Post-translational modifications (4): 69, 83, 85, 114

Function

Pathways and Gene Ontology

Reactome pathways

64 pathways

ID	Pathway
R-HSA-163615	PKA activation
R-HSA-164378	PKA activation in glucagon signalling
R-HSA-180024	DARPP-32 events
R-HSA-2565942	Regulation of PLK1 Activity at G2/M Transition
R-HSA-380259	Loss of Nlp from mitotic centrosomes
R-HSA-380270	Recruitment of mitotic centrosome proteins and complexes
R-HSA-380284	Loss of proteins required for interphase microtubule organization from the centrosome
R-HSA-380320	Recruitment of NuMA to mitotic centrosomes
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-442720	CREB1 phosphorylation through the activation of Adenylate Cyclase
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-8854518	AURKA Activation by TPX2
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
R-HSA-109582	Hemostasis
R-HSA-111885	Opioid Signalling
R-HSA-111931	PKA-mediated phosphorylation of CREB
R-HSA-111933	Calmodulin induced events
R-HSA-111996	Ca-dependent events
R-HSA-111997	CaM pathway
R-HSA-112040	G-protein mediated events
R-HSA-112043	PLC beta mediated events
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System

MSigDB gene sets: 495 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_COGNITION, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_BEHAVIOR, MODULE_169, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, GOBP_CELLULAR_RESPONSE_TO_FLUID_SHEAR_STRESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR

GO Biological Process (13): negative regulation of inflammatory response to antigenic stimulus (GO:0002862), renal water homeostasis (GO:0003091), fatty acid metabolic process (GO:0006631), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), chemical synaptic transmission (GO:0007268), learning (GO:0007612), intracellular signal transduction (GO:0035556), modulation of chemical synaptic transmission (GO:0050804), cellular response to glucagon stimulus (GO:0071377), response to antipsychotic drug (GO:0097332), vascular endothelial cell response to laminar fluid shear stress (GO:0097700), negative regulation of cAMP/PKA signal transduction (GO:0141162), regulation of protein phosphorylation (GO:0001932)

GO Molecular Function (9): cAMP-dependent protein kinase inhibitor activity (GO:0004862), cAMP-dependent protein kinase regulator activity (GO:0008603), protein domain specific binding (GO:0019904), cAMP binding (GO:0030552), ubiquitin protein ligase binding (GO:0031625), protein kinase A catalytic subunit binding (GO:0034236), nucleotide binding (GO:0000166), protein binding (GO:0005515), protein kinase binding (GO:0019901)

GO Cellular Component (15): cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), cAMP-dependent protein kinase complex (GO:0005952), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), dendritic shaft (GO:0043198), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), ciliary base (GO:0097546), glutamatergic synapse (GO:0098978), membrane (GO:0016020), dendrite (GO:0030425), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
G2/M Transition	2
Centrosome maturation	2
Anti-inflammatory response favouring Leishmania parasite infection	2
PKA-mediated phosphorylation of CREB	1
Glucagon signaling in metabolic regulation	1
Opioid Signalling	1
Loss of proteins required for interphase microtubule organization from the centrosome	1
Mitotic Prometaphase	1
Regulation of insulin secretion	1
Aquaporin-mediated transport	1
Post NMDA receptor activation events	1
Signaling by Hedgehog	1
Assembly of the 9+0 primary cilium	1
G alpha (s) signalling events	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
intracellular anatomical structure	2
cAMP-dependent protein kinase activity	2
cytoplasm	2
dendrite	2
synapse	2
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
renal system process	1
multicellular organismal-level water homeostasis	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
anterograde trans-synaptic signaling	1
learning or memory	1
signal transduction	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
response to glucagon	1
cellular response to peptide hormone stimulus	1
response to chemical	1
cellular response to laminar fluid shear stress	1
vascular endothelial cell response to fluid shear stress	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
protein phosphorylation	1
regulation of protein modification process	1
regulation of phosphorylation	1
cAMP-dependent protein kinase regulator activity	1
protein serine/threonine kinase inhibitor activity	1
protein kinase regulator activity	1
protein binding	1
cyclic nucleotide binding	1
adenyl ribonucleotide binding	1
anion binding	1
ubiquitin-like protein ligase binding	1

Protein interactions and networks

STRING

2192 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRKAR2B	AKAP5	P24588	967
PRKAR2B	PRKACA	P17612	932
PRKAR2B	PRKACB	P22694	927
PRKAR2B	PRKACG	P22612	919
PRKAR2B	AKAP1	Q92667	884
PRKAR2B	PRKX	P51817	775
PRKAR2B	CFAP91	Q7Z4T9	762
PRKAR2B	AKAP10	O43572	711
PRKAR2B	AKAP9	Q99996	614
PRKAR2B	KLHL5	Q96PQ7	571
PRKAR2B	AKAP7	O43687	558
PRKAR2B	PALM2AKAP2	Q9Y2D5	555
PRKAR2B	AKAP8	O43823	544
PRKAR2B	AKAP11	Q9UKA4	543
PRKAR2B	FASN	P49327	522

IntAct

178 interactions, top by confidence:

A	B	Type	Score
PRKACA	PRKAR2B	psi-mi:“MI:0915”(physical association)	0.960
PRKACA	PRKAR2B	psi-mi:“MI:0407”(direct interaction)	0.960
PRKAR2B	PRKACA	psi-mi:“MI:0915”(physical association)	0.960
PRKAR2B	PRKACA	psi-mi:“MI:2364”(proximity)	0.960
MAPRE1	CLASP2	psi-mi:“MI:0914”(association)	0.850
CSNK1E	PER2	psi-mi:“MI:0914”(association)	0.850
CSNK1D	PER2	psi-mi:“MI:0914”(association)	0.810
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
IFT70B	IFT56	psi-mi:“MI:0914”(association)	0.790
PRKAR2B	AKAP14	psi-mi:“MI:0915”(physical association)	0.740
PRKACA	VAPB	psi-mi:“MI:0914”(association)	0.730
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
	PRKAR1A	psi-mi:“MI:0914”(association)	0.700
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
KIFAP3	KIF3C	psi-mi:“MI:0914”(association)	0.640
AKAP7	PRKAR2B	psi-mi:“MI:0915”(physical association)	0.630

BioGRID (265): PRKAR2B (Two-hybrid), TAF12 (Two-hybrid), AKAP7 (Two-hybrid), PRKAR2B (Affinity Capture-MS), AKAP1 (Affinity Capture-MS), AKAP11 (Affinity Capture-MS), PRKAR2A (Affinity Capture-MS), AKAP9 (Affinity Capture-MS), AKAP13 (Affinity Capture-MS), PDE4DIP (Affinity Capture-MS), CDK5RAP2 (Affinity Capture-MS), PRKACA (Affinity Capture-MS), PRKACG (Affinity Capture-MS), PRKACB (Affinity Capture-MS), AKAP2 (Affinity Capture-MS)

ESM2 similar proteins: A0JVA0, A0QTP2, A0QX51, A1A0A3, A1A3P4, A1R5G4, A1UER9, A3PY76, A6WE36, A9WRD2, B1VYN3, B1W5F4, B3DQ30, B7GPW0, B8DT61, B8DTW1, B8HGX6, C3PGM1, O43102, O53873, O60832, O76031, O86810, P0A9M8, P0A9M9, P12369, P31322, P31323, P31324, P40615, P55011, P55012, P9WGJ0, P9WGJ1, P9WNA2, P9WNA3, Q06364, Q1BA93, Q5R7N3, Q5U2U0

Diamond homologs: A0A509AKL0, A0R3F9, A5K0N4, O14448, O42794, O59922, P00514, P00515, P00516, P05207, P05987, P07278, P07802, P09456, P0C605, P10644, P12367, P12368, P12369, P12849, P13861, P16905, P30625, P31319, P31320, P31321, P31322, P31323, P31324, P32023, P34578, P36600, P49605, P81377, P81900, P86244, Q01386, Q03042, Q13976, Q26619

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PRKACA	“up-regulates activity”	PRKAR2B	phosphorylation
PRKAR2B	“down-regulates activity”	PRKACA	binding
PRKAR2B	“down-regulates activity”	PRKACB	binding
“3’,5’-cyclic AMP”	“down-regulates activity”	PRKAR2B	“chemical inhibition”
PJA2	“down-regulates quantity by destabilization”	PRKAR2B	polyubiquitination
PRKAR2B	“up-regulates activity”	PRKAR2B	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 146 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
PKA activation	6	41.8×	3e-07
PKA-mediated phosphorylation of CREB	6	37.6×	4e-07
PKA activation in glucagon signalling	5	36.9×	4e-06
DARPP-32 events	6	31.4×	1e-06
Anti-inflammatory response favouring Leishmania parasite infection	6	26.0×	3e-06
Leishmania parasite growth and survival	6	26.0×	3e-06
Calmodulin induced events	6	25.1×	3e-06
CaM pathway	6	25.1×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
vascular endothelial cell response to laminar fluid shear stress	5	28.2×	7e-04
renal water homeostasis	5	19.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2453 predictions. Top by Δscore:

Variant	Effect	Δscore
7:107070276:TTTA:T	acceptor_loss	1.0000
7:107070279:A:AG	acceptor_gain	1.0000
7:107070279:AGCT:A	acceptor_loss	1.0000
7:107070280:G:A	acceptor_loss	1.0000
7:107070280:G:GG	acceptor_gain	1.0000
7:107070316:GGTA:G	donor_loss	1.0000
7:107070317:G:GG	donor_gain	1.0000
7:107070318:T:G	donor_loss	1.0000
7:107121949:TA:T	acceptor_loss	1.0000
7:107121950:A:AG	acceptor_gain	1.0000
7:107121950:AGTAT:A	acceptor_gain	1.0000
7:107121951:G:A	acceptor_loss	1.0000
7:107121951:G:GC	acceptor_gain	1.0000
7:107121951:GT:G	acceptor_gain	1.0000
7:107121951:GTA:G	acceptor_gain	1.0000
7:107121951:GTAT:G	acceptor_gain	1.0000
7:107121951:GTATG:G	acceptor_gain	1.0000
7:107122003:GG:G	donor_gain	1.0000
7:107122004:GG:G	donor_gain	1.0000
7:107122004:GGT:G	donor_loss	1.0000
7:107122005:G:GG	donor_gain	1.0000
7:107122005:GT:G	donor_loss	1.0000
7:107122006:T:TC	donor_loss	1.0000
7:107150921:GGACA:G	acceptor_gain	1.0000
7:107153172:TGTAG:T	acceptor_loss	1.0000
7:107153174:TAGTT:T	acceptor_loss	1.0000
7:107153175:A:AG	acceptor_gain	1.0000
7:107153175:AGT:A	acceptor_loss	1.0000
7:107153176:G:GT	acceptor_gain	1.0000
7:107153176:GT:G	acceptor_gain	1.0000

AlphaMissense

2761 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:107128226:A:C	K137N	1.000
7:107128226:A:T	K137N	1.000
7:107146309:G:C	G197R	1.000
7:107146310:G:T	G197V	1.000
7:107146381:T:C	F221L	1.000
7:107146383:C:A	F221L	1.000
7:107146383:C:G	F221L	1.000
7:107146384:G:C	G222R	1.000
7:107146384:G:T	G222C	1.000
7:107146385:G:A	G222D	1.000
7:107146385:G:T	G222V	1.000
7:107146391:T:A	L224Q	1.000
7:107146391:T:C	L224P	1.000
7:107146394:C:A	A225D	1.000
7:107146397:T:C	L226S	1.000
7:107146415:G:C	R232T	1.000
7:107146415:G:T	R232I	1.000
7:107146416:A:C	R232S	1.000
7:107146416:A:T	R232S	1.000
7:107146420:G:C	A234P	1.000
7:107146421:C:A	A234D	1.000
7:107146427:T:A	I236N	1.000
7:107146453:T:A	W245R	1.000
7:107146453:T:C	W245R	1.000
7:107150934:T:C	F252L	1.000
7:107150936:C:A	F252L	1.000
7:107150936:C:G	F252L	1.000
7:107157253:G:A	G351E	1.000
7:107159476:T:C	L384P	1.000
7:107044945:T:C	L13P	0.999

dbSNP variants (sampled 300 via entrez): RS1000008348 (7:107060839 C>T), RS1000029448 (7:107148090 G>A), RS1000054122 (7:107142562 C>G), RS1000061258 (7:107053227 G>A), RS1000077801 (7:107142531 T>G), RS1000119294 (7:107120768 A>C), RS1000137801 (7:107100047 A>C,G), RS1000163591 (7:107124061 A>G), RS1000169515 (7:107122799 T>C), RS1000181234 (7:107157550 A>G), RS1000199962 (7:107044733 G>C), RS1000218934 (7:107075201 C>T), RS1000271993 (7:107084976 A>G), RS1000318389 (7:107117624 C>G), RS1000337513 (7:107111277 G>A)

Disease associations

OMIM: gene MIM:176912 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000618_35	Response to antipsychotic treatment	6.000000e-08
GCST001431_8	Adverse response to lamotrigine and phenytoin	6.000000e-06
GCST002397_3	Bladder cancer (smoking interaction)	6.000000e-06
GCST002932_28	Manganese levels	2.000000e-06
GCST008062_18	Blood urea nitrogen levels	7.000000e-11
GCST008163_385	Height	2.000000e-06
GCST010244_426	Triglyceride levels	1.000000e-09
GCST012490_625	Femur bone mineral density x serum urate levels interaction	8.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2270 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Protein kinase A (PKA) family

Binding affinities (BindingDB)

1 measured of 1 human assays (10 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
5-[(2E)-2-(8-oxidanylidenequinolin-5-ylidene)hydrazinyl]naphthalene-1-sulfonic acid	IC50	1700 nM

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.12	Kd	75	nM	CHEMBL4203735
6.91	Kd	124	nM	CHEMBL4204708
6.88	Kd	131	nM	CHEMBL4211508
6.83	Kd	147	nM	CHEMBL4207455
6.82	Kd	152	nM	CHEMBL4215761
6.59	Kd	257	nM	CHEMBL4204281
6.25	Kd	557	nM	CHEMBL4205523

PubChem BioAssay actives

21 with measured affinity, of 572 total; 14 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
sodium (4aR,6R,7R,7aS)-6-[6-amino-8-(4-chlorophenyl)sulfanylpurin-9-yl]-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	504888: Fluorescence polarization-based biochemical high throughput dose response assay for activators of the Protein Kinase A-R2B (PKA-R2B) complex	ec50	0.0505	uM
sodium (4aR,6R,7R,7aS)-6-(6-amino-8-bromopurin-9-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	504888: Fluorescence polarization-based biochemical high throughput dose response assay for activators of the Protein Kinase A-R2B (PKA-R2B) complex	ec50	0.0511	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,15E,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-8-(4-aminobutyl)-2,11,20-trimethyl-5-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carbonyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid	1374580: Binding affinity to recombinant human full length PKA-R2beta expressed in Escherichia coli BL21 DE3-RIL cells assessed as reduction in interaction with AKAP by fluorescence polarization analysis	kd	0.0750	uM
sodium (4aR,6R,7R,7aS)-6-(6-aminopurin-9-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	504888: Fluorescence polarization-based biochemical high throughput dose response assay for activators of the Protein Kinase A-R2B (PKA-R2B) complex	ec50	0.0885	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,15E,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-8-(4-aminobutyl)-2,11,20-trimethyl-5-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carbonyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid	1374580: Binding affinity to recombinant human full length PKA-R2beta expressed in Escherichia coli BL21 DE3-RIL cells assessed as reduction in interaction with AKAP by fluorescence polarization analysis	kd	0.1240	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,15E,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]propanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-8-(4-aminobutyl)-2,11,20-trimethyl-5-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carbonyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid	1374580: Binding affinity to recombinant human full length PKA-R2beta expressed in Escherichia coli BL21 DE3-RIL cells assessed as reduction in interaction with AKAP by fluorescence polarization analysis	kd	0.1310	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,15E,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-2,8,11,20-tetramethyl-5-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carbonyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid	1374580: Binding affinity to recombinant human full length PKA-R2beta expressed in Escherichia coli BL21 DE3-RIL cells assessed as reduction in interaction with AKAP by fluorescence polarization analysis	kd	0.1470	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,15E,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-8-(4-aminobutyl)-2,11,20-trimethyl-5-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carbonyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid	1374580: Binding affinity to recombinant human full length PKA-R2beta expressed in Escherichia coli BL21 DE3-RIL cells assessed as reduction in interaction with AKAP by fluorescence polarization analysis	kd	0.1520	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,15E,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]hexanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-8-(4-aminobutyl)-2,11,20-trimethyl-5-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carbonyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid	1374580: Binding affinity to recombinant human full length PKA-R2beta expressed in Escherichia coli BL21 DE3-RIL cells assessed as reduction in interaction with AKAP by fluorescence polarization analysis	kd	0.2570	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,15E,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-8-(4-aminobutyl)-2,11,20-trimethyl-5-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carbonyl]amino]propanoyl]amino]propanoyl]amino]hexanoic acid	1374580: Binding affinity to recombinant human full length PKA-R2beta expressed in Escherichia coli BL21 DE3-RIL cells assessed as reduction in interaction with AKAP by fluorescence polarization analysis	kd	0.5570	uM
sodium 9-[(4aR,6R,7R,7aS)-7-hydroxy-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl]-2-amino-8-bromo-1H-purin-6-one	504888: Fluorescence polarization-based biochemical high throughput dose response assay for activators of the Protein Kinase A-R2B (PKA-R2B) complex	ec50	2.1550	uM
6-(6-aminopurin-9-yl)-2-ethoxy-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	504888: Fluorescence polarization-based biochemical high throughput dose response assay for activators of the Protein Kinase A-R2B (PKA-R2B) complex	ec50	3.7540	uM
sodium [(4aR,6R,7R,7aR)-6-[6-(butanoylamino)purin-9-yl]-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-yl] butanoate	504888: Fluorescence polarization-based biochemical high throughput dose response assay for activators of the Protein Kinase A-R2B (PKA-R2B) complex	ec50	5.3780	uM
sodium;[(4aS,5R,6R,7aR)-6-[6-(butanoylamino)purin-9-yl]-2-oxido-2-oxo-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3,2]dioxaphosphinin-5-yl] butanoate;hydrate	504888: Fluorescence polarization-based biochemical high throughput dose response assay for activators of the Protein Kinase A-R2B (PKA-R2B) complex	ec50	9.1020	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression	4
(+)-JQ1 compound	increases expression	3
Benzo(a)pyrene	affects methylation, increases expression	3
bisphenol A	increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Dexamethasone	increases expression, affects cotreatment	2
Doxorubicin	affects expression, increases expression, affects reaction, decreases expression, decreases reaction	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
mivebresib	increases expression	1
triphenyl phosphate	affects expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
methylselenic acid	increases expression	1
trichostatin A	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
pentanal	increases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
casticin	decreases expression	1
cyanoginosin LR	increases methylation, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4188747	Binding	Binding affinity to recombinant human full length PKA-R2beta expressed in Escherichia coli BL21 DE3-RIL cells assessed as reduction in interaction with AKAP by fluorescence polarization analysis	Investigating PKA-RII specificity using analogs of the PKA:AKAP peptide inhibitor STAD-2. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_IM66	OVCAR-8 RIIB	Cancer cell line	Female

Clinical trials (associated diseases)

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