PKIA

Summary

PKIA (cAMP-dependent protein kinase inhibitor alpha, HGNC:9017) is a protein-coding gene on chromosome 8q21.13, encoding cAMP-dependent protein kinase inhibitor alpha (P61925). Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains.

The protein encoded by this gene is a member of the cAMP-dependent protein kinase (PKA) inhibitor family. This protein was demonstrated to interact with and inhibit the activities of both C alpha and C beta catalytic subunits of the PKA. Alternatively spliced transcript variants encoding the same protein have been reported.

Source: NCBI Gene 5569 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 9 total
• MANE Select transcript: NM_006823

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9017
Approved symbol	PKIA
Name	cAMP-dependent protein kinase inhibitor alpha
Location	8q21.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000171033
Ensembl biotype	protein_coding
OMIM	606059
Entrez	5569

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 27 protein_coding

ENST00000352966, ENST00000396418, ENST00000518467, ENST00000863444, ENST00000911760, ENST00000911761, ENST00000911762, ENST00000911763, ENST00000911764, ENST00000911765, ENST00000911766, ENST00000959522, ENST00000959523, ENST00000959524, ENST00000959525, ENST00000959526, ENST00000959527, ENST00000959528, ENST00000959529, ENST00000959530, ENST00000959531, ENST00000959532, ENST00000959533, ENST00000959534, ENST00000959535, ENST00000959536, ENST00000959537

RefSeq mRNA: 2 — MANE Select: NM_006823 NM_006823, NM_181839

CCDS: CCDS6222

Canonical transcript exons

ENST00000396418 — 4 exons

Exon	Start	End
ENSE00001167467	78598358	78598535
ENSE00001524870	78572811	78572939
ENSE00001524871	78516340	78516468
ENSE00002091070	78601742	78605267

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 99.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.8598 / max 645.3773, expressed in 1465 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89464	15.5289	1455
89467	2.3744	71
89465	0.4897	255
89466	0.4668	257

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	99.54	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.40	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.37	gold quality
cortical plate	UBERON:0005343	99.26	gold quality
vastus lateralis	UBERON:0001379	99.20	gold quality
quadriceps femoris	UBERON:0001377	99.07	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.07	gold quality
diaphragm	UBERON:0001103	99.04	gold quality
skeletal muscle tissue	UBERON:0001134	98.92	gold quality
deltoid	UBERON:0001476	98.58	gold quality
triceps brachii	UBERON:0001509	98.41	gold quality
heart right ventricle	UBERON:0002080	98.39	gold quality
left ventricle myocardium	UBERON:0006566	98.21	gold quality
body of tongue	UBERON:0011876	98.19	gold quality
gastrocnemius	UBERON:0001388	98.13	gold quality
gluteal muscle	UBERON:0002000	98.02	gold quality
tibialis anterior	UBERON:0001385	97.99	gold quality
muscle organ	UBERON:0001630	97.87	gold quality
muscle of leg	UBERON:0001383	97.34	gold quality
CA1 field of hippocampus	UBERON:0003881	97.10	gold quality
ganglionic eminence	UBERON:0004023	97.09	gold quality
muscle tissue	UBERON:0002385	96.43	gold quality
entorhinal cortex	UBERON:0002728	96.38	gold quality
myocardium	UBERON:0002349	96.31	gold quality
nucleus accumbens	UBERON:0001882	95.92	gold quality
cardiac ventricle	UBERON:0002082	95.72	gold quality
heart left ventricle	UBERON:0002084	95.66	gold quality
temporal lobe	UBERON:0001871	95.42	gold quality
ventricular zone	UBERON:0003053	95.25	gold quality
amygdala	UBERON:0001876	95.19	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	16.84
E-ANND-3	yes	4.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

190 targeting PKIA, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580

Literature-anchored findings (GeneRIF, showing 1)

• Exploring the methylation status of CFTR and PKIA genes as potential biomarkers for lung adenocarcinoma. (PMID:37644544)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pkia	ENSMUSG00000027499
rattus_norvegicus	Pkia	ENSRNOG00000012095

Paralogs (2): PKIB (ENSG00000135549), PKIG (ENSG00000168734)

Protein

Protein identifiers

cAMP-dependent protein kinase inhibitor alpha — P61925 (reviewed: P61925)

Alternative names: cAMP-dependent protein kinase inhibitor, muscle/brain isoform

All UniProt accessions (1): P61925

UniProt curated annotations — full annotation on UniProt →

Function. Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains.

Miscellaneous. The inhibitory site contains regions very similar to the hinge regions (sites that directly interact with the enzyme active site) and ‘pseudosubstrate site’ of the regulatory chains; but, unlike these chains, PKI does not contain cAMP-binding sites. The arginine residues within the inhibitory site are essential for inhibition and recognition of the enzyme active site.

Similarity. Belongs to the PKI family.

RefSeq proteins (2): NP_006814, NP_862822 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004171	cAMP_dep_PKI	Family

Pfam: PF02827

Enzyme classification (BRENDA):

• EC 2.7.11.11 — cAMP-dependent protein kinase (BRENDA: 43 organisms, 244 substrates, 131 inhibitors, 50 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
KEMPTIDE	0.0097–0.0609	11
ATP	0.0169–0.039	9
LEU-ARG-ARG-ALA-SER-LEU-GLY	0.023–0.043	4
N6-BENZYL-ATP	0.0011–0.1	2
PEPTIDE RRYSV	0.027–0.029	2
RFARKGSLREKNV	0.0253–0.05	2
RKRSRAE	0.0333–0.293	2
RKRSRKE	0.0333–0.5	2
RRLSSLRA	0.0503–0.338	2
HISTONE	0.73	1
N-(8-([4-[3-(ETHOXYCARBONYL)-6,8,8-TRIMETHYL-2-O	0.0019	1
N-(8-([[7-(DIETHYLAMINO)-2-OXO-2H-CHROMEN-3-YL]C	0.0022	1
N-(8-[[(11-OXO-2,3,6,7-TETRAHYDRO-1H,5H,11H-PYRA	0.0062	1
N6-PHENETHYL-ATP	0.0015	1
RRASVA	0.021	1

UniProt features (12 total): helix 3, site 3, strand 2, initiator methionine 1, chain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

117 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5M6Y	X-RAY DIFFRACTION	1.37
5M6V	X-RAY DIFFRACTION	1.42
5LCQ	X-RAY DIFFRACTION	1.42
5LCP	X-RAY DIFFRACTION	1.43
5M0L	X-RAY DIFFRACTION	1.47
5M71	X-RAY DIFFRACTION	1.49
5M0B	X-RAY DIFFRACTION	1.51
5M75	X-RAY DIFFRACTION	1.54
4IAI	X-RAY DIFFRACTION	1.55
4WB8	X-RAY DIFFRACTION	1.55
9PC1	X-RAY DIFFRACTION	1.55
4Z84	X-RAY DIFFRACTION	1.55
5LCR	X-RAY DIFFRACTION	1.56
5LCU	X-RAY DIFFRACTION	1.58
3OVV	X-RAY DIFFRACTION	1.58
1XH8	X-RAY DIFFRACTION	1.6
3POO	X-RAY DIFFRACTION	1.6
4IAK	X-RAY DIFFRACTION	1.6
5LCT	X-RAY DIFFRACTION	1.61
4IB1	X-RAY DIFFRACTION	1.63
7V0G	X-RAY DIFFRACTION	1.63
1XH9	X-RAY DIFFRACTION	1.64
4WB5	X-RAY DIFFRACTION	1.64
5M0U	X-RAY DIFFRACTION	1.67
6QJ7	X-RAY DIFFRACTION	1.69
3X2W	X-RAY DIFFRACTION	1.7
4O22	X-RAY DIFFRACTION	1.7
5M0C	X-RAY DIFFRACTION	1.73
3AMA	X-RAY DIFFRACTION	1.75
4UJ1	X-RAY DIFFRACTION	1.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61925-F1	65.68	0.02

Functional residue map

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

Catalytic / active sites (3): 16 (important for inhibition); 19 (important for inhibition); 20 (important for inhibition)

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 306 (showing top): MODULE_52, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, MODULE_255, TGCACTT_MIR519C_MIR519B_MIR519A, GOZGIT_ESR1_TARGETS_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, MODULE_317, TATTATA_MIR374, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GGGTGGRR_PAX4_03, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of G2/M transition of mitotic cell cycle (GO:0010389), negative regulation of protein import into nucleus (GO:0042308), negative regulation of cAMP/PKA signal transduction (GO:0141162), negative regulation of cAMP-dependent protein kinase activity (GO:2000480), negative regulation of protein kinase activity (GO:0006469)

GO Molecular Function (4): cAMP-dependent protein kinase inhibitor activity (GO:0004862), protein kinase A catalytic subunit binding (GO:0034236), protein kinase inhibitor activity (GO:0004860), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cAMP-dependent protein kinase activity	2
protein kinase activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
G2/M transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of cell cycle G2/M phase transition	1
protein import into nucleus	1
regulation of protein import into nucleus	1
negative regulation of nucleocytoplasmic transport	1
negative regulation of intracellular protein transport	1
negative regulation of protein localization to nucleus	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
negative regulation of protein serine/threonine kinase activity	1
regulation of cAMP-dependent protein kinase activity	1
negative regulation of protein phosphorylation	1
negative regulation of kinase activity	1
regulation of protein kinase activity	1
cAMP-dependent protein kinase regulator activity	1
protein serine/threonine kinase inhibitor activity	1
protein kinase binding	1
protein kinase A binding	1
kinase inhibitor activity	1
protein kinase regulator activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

48 interactions, top by confidence:

A	B	Type	Score
PRKACA	VAPB	psi-mi:“MI:0914”(association)	0.730
Xpo1	PKIA	psi-mi:“MI:0407”(direct interaction)	0.650
PKIA	DYNLL1	psi-mi:“MI:0915”(physical association)	0.560
PKIA	DYNLL2	psi-mi:“MI:0915”(physical association)	0.560
PRKACB	PKIA	psi-mi:“MI:0915”(physical association)	0.560
PRC1	PKIA	psi-mi:“MI:0915”(physical association)	0.560
CASP6	PKIA	psi-mi:“MI:0915”(physical association)	0.560
PKIA	MRNIP	psi-mi:“MI:0915”(physical association)	0.560
PKIA	RAN	psi-mi:“MI:0915”(physical association)	0.520
CRM1	PKIA	psi-mi:“MI:0915”(physical association)	0.520
PKIA	CRM1	psi-mi:“MI:0915”(physical association)	0.520
PASK	PKIA	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
XPO1	PKIA	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (17): PKIA (Synthetic Growth Defect), GSP1 (Co-crystal Structure), CRM1 (Co-crystal Structure), XPO1 (Protein-peptide), XPO1 (Reconstituted Complex), PKIA (Two-hybrid), PKIA (Two-hybrid), PKIA (Two-hybrid), PKIA (Two-hybrid), PRC1 (Two-hybrid), DYNLL2 (Two-hybrid), PKIA (Reconstituted Complex), PKIA (Affinity Capture-MS), PKIA (Affinity Capture-MS), PKIA (Protein-peptide)

ESM2 similar proteins: A0A1B0GUA9, A0A1B0GV96, A4IFJ0, B3DGJ2, O43687, O55074, O70139, O75167, P04370, P0C8S0, P0C913, P0C914, P0CD96, P19103, P27775, P49342, P61925, P61926, P62025, P63248, P63249, Q04758, Q13522, Q29026, Q3SX13, Q3T0A6, Q3ZB98, Q4VC05, Q5FVI4, Q5R6X9, Q64256, Q6P3A1, Q71U53, Q7M2N1, Q7YQJ3, Q7YQJ4, Q8N111, Q8R409, Q8TAD7, Q8WMS3

Diamond homologs: O70139, P61925, P61926, P63248, P63249, Q3SX13, Q71U53, Q7YQJ3, Q7YQJ4, Q90641, Q9Y2B9, P27775, Q04758, Q9C010

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EGFR	up-regulates	PKIA	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1825 predictions. Top by Δscore:

Variant	Effect	Δscore
8:78598353:TGTA:T	acceptor_loss	1.0000
8:78598354:GTAGT:G	acceptor_loss	1.0000
8:78598356:A:AG	acceptor_gain	1.0000
8:78598356:AG:A	acceptor_loss	1.0000
8:78598357:G:C	acceptor_loss	1.0000
8:78598357:G:GT	acceptor_gain	1.0000
8:78598357:GT:G	acceptor_gain	1.0000
8:78598357:GTC:G	acceptor_gain	1.0000
8:78598357:GTCC:G	acceptor_gain	1.0000
8:78598357:GTCCC:G	acceptor_gain	1.0000
8:78598531:GACAG:G	donor_gain	1.0000
8:78598532:ACAGG:A	donor_loss	1.0000
8:78598533:CAGGT:C	donor_loss	1.0000
8:78598534:AGG:A	donor_loss	1.0000
8:78598536:G:C	donor_loss	1.0000
8:78598536:G:GG	donor_gain	1.0000
8:78598537:T:A	donor_loss	1.0000
8:78601737:T:TA	acceptor_gain	1.0000
8:78601740:A:AG	acceptor_gain	1.0000
8:78601740:AG:A	acceptor_loss	1.0000
8:78601740:AGAAG:A	acceptor_gain	1.0000
8:78601741:G:GT	acceptor_gain	1.0000
8:78601741:GA:G	acceptor_gain	1.0000
8:78601741:GAA:G	acceptor_gain	1.0000
8:78601741:GAAGG:G	acceptor_gain	1.0000
8:78516466:AAGG:A	donor_loss	0.9900
8:78516469:GT:G	donor_loss	0.9900
8:78516470:T:A	donor_loss	0.9900
8:78527139:TAAA:T	donor_gain	0.9900
8:78527140:AAAA:A	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000024601 (8:78555263 C>A,G,T), RS1000030250 (8:78599080 T>C), RS1000038264 (8:78562310 T>C), RS1000070211 (8:78545649 T>G), RS1000108543 (8:78536492 A>G), RS1000118428 (8:78536869 C>T), RS1000175380 (8:78589230 A>G), RS1000201845 (8:78535570 G>T), RS1000255778 (8:78535872 T>C), RS1000269312 (8:78580148 G>A,T), RS1000270216 (8:78588950 T>A,C), RS1000339461 (8:78595592 A>G), RS1000348249 (8:78529709 T>C), RS1000381147 (8:78550725 T>C), RS1000459727 (8:78555728 A>G)

Disease associations

OMIM: gene MIM:606059 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001198_67	Multiple sclerosis	2.000000e-07
GCST003807_7	Systolic blood pressure response to hydrochlorothiazide in hypertension	7.000000e-06
GCST005580_161	Intraocular pressure	9.000000e-09
GCST005580_67	Intraocular pressure	6.000000e-12
GCST005752_162	Systemic lupus erythematosus	3.000000e-08
GCST007400_11	Systemic lupus erythematosus	1.000000e-07
GCST007691_5	Femoral neck bone mineral density	6.000000e-07
GCST009462_97	Optic disc size	2.000000e-10
GCST009725_62	Intraocular pressure	6.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006944	systolic blood pressure change measurement
EFO:0004695	intraocular pressure measurement
EFO:0007785	femoral neck bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases methylation	2
trichostatin A	affects cotreatment, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Doxorubicin	decreases expression, affects response to substance	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	decreases methylation	1
afimoxifene	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
hydroquinone	decreases expression	1
beta-methylcholine	affects expression	1
arsenic disulfide	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, decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
MRK 003	decreases expression	1
incobotulinumtoxinA	decreases expression	1
Bortezomib	increases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Cyclic AMP	affects binding, affects response to substance, decreases stability	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects methylation	1
Carbamazepine	affects expression	1
Cytarabine	decreases expression	1

Clinical trials (associated diseases)

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