PPP1R14A

Summary

PPP1R14A (protein phosphatase 1 regulatory inhibitor subunit 14A, HGNC:14871) is a protein-coding gene on chromosome 19q13.1, encoding Protein phosphatase 1 regulatory subunit 14A (Q96A00). Inhibitor of PPP1CA.

The protein encoded by this gene belongs to the protein phosphatase 1 (PP1) inhibitor family. This protein is an inhibitor of smooth muscle myosin phosphatase, and has higher inhibitory activity when phosphorylated. Inhibition of myosin phosphatase leads to increased myosin phosphorylation and enhanced smooth muscle contraction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 94274 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 39 total
• MANE Select transcript: NM_033256

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14871
Approved symbol	PPP1R14A
Name	protein phosphatase 1 regulatory inhibitor subunit 14A
Location	19q13.1
Locus type	gene with protein product
Status	Approved
Aliases	CPI-17
Ensembl gene	ENSG00000167641
Ensembl biotype	protein_coding
OMIM	608153
Entrez	94274

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000301242, ENST00000347262, ENST00000587515, ENST00000591291, ENST00000591585, ENST00000915262, ENST00000956130

RefSeq mRNA: 2 — MANE Select: NM_033256 NM_001243947, NM_033256

CCDS: CCDS12509, CCDS58660

Canonical transcript exons

ENST00000301242 — 4 exons

Exon	Start	End
ENSE00001115175	38252894	38252974
ENSE00001115177	38252306	38252338
ENSE00001115178	38256139	38256374
ENSE00001296396	38251237	38251446

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 99.78.

FANTOM5 (CAGE): breadth broad, TPM avg 15.0405 / max 666.3490, expressed in 899 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180758	9.0744	826
180760	4.4209	692
180754	1.1540	135
180759	0.3129	160
180753	0.0539	24
180752	0.0245	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	99.78	gold quality
ascending aorta	UBERON:0001496	99.77	gold quality
thoracic aorta	UBERON:0001515	99.77	gold quality
popliteal artery	UBERON:0002250	99.76	gold quality
tibial artery	UBERON:0007610	99.75	gold quality
aorta	UBERON:0000947	99.74	gold quality
descending thoracic aorta	UBERON:0002345	99.66	gold quality
left coronary artery	UBERON:0001626	99.64	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.62	gold quality
coronary artery	UBERON:0001621	99.61	gold quality
saphenous vein	UBERON:0007318	99.58	gold quality
spinal cord	UBERON:0002240	99.53	gold quality
inferior vagus X ganglion	UBERON:0005363	99.43	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.41	gold quality
lower esophagus	UBERON:0013473	99.40	gold quality
mucosa of stomach	UBERON:0001199	99.30	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.29	gold quality
right lung	UBERON:0002167	99.18	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.06	gold quality
substantia nigra	UBERON:0002038	98.73	gold quality
midbrain	UBERON:0001891	98.70	gold quality
body of uterus	UBERON:0009853	98.66	gold quality
left uterine tube	UBERON:0001303	98.64	gold quality
medulla oblongata	UBERON:0001896	98.63	gold quality
right adrenal gland	UBERON:0001233	98.62	gold quality
right adrenal gland cortex	UBERON:0035827	98.57	gold quality
pons	UBERON:0000988	98.51	gold quality
left adrenal gland cortex	UBERON:0035825	98.50	gold quality
left adrenal gland	UBERON:0001234	98.38	gold quality
subthalamic nucleus	UBERON:0001906	98.34	gold quality

Single-cell (SCXA)

Detected in 21 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	3927.68
E-HCAD-36	yes	2168.04
E-HCAD-25	yes	1357.28
E-MTAB-6308	yes	1202.28
E-MTAB-3929	yes	918.44
E-HCAD-56	yes	766.36
E-CURD-79	yes	429.40
E-MTAB-6701	yes	119.32
E-MTAB-10287	yes	79.36
E-HCAD-6	yes	59.73
E-HCAD-1	yes	43.45
E-MTAB-8410	yes	34.11
E-CURD-112	yes	32.98
E-GEOD-135922	yes	29.48
E-GEOD-84465	yes	14.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA6, NFKB, PPARG, SP1, SP3

Literature-anchored findings (GeneRIF, showing 23)

• mapped to chromosome 19q13.13-q13.2 (PMID:11931393)
• CPI-17 binds directly to protein kinase C and casein kinase I. (PMID:15003508)
• importance of PKC/CPI-17-mediated pathway in histamine-triggered cytoskeletal rearrangements leading to lung microvascular barrier compromise. (PMID:15234908)
• CPI-17 siRNA decreased the level of merlin phosphorylation and consequently Ras and ERK activity in human tumor cell lines (PMID:16885985)
• These data indicate that 14,15-epoxyeicosatrienoic acid hyperpolarizes airway smooth muscle cells and relaxes precontracted human bronchi and intracellular effects are related to a PKC-dependent process involving a lower phosphorylation level of CPI-17. (PMID:17237191)
• Human pregnancy is characterized by increases in PKN1 expression and PPP1R14A phosphorylation in the myometrium. (PMID:17301291)
• These results are consistent with a key molecular role for CPI-17 in airway hyperresponsiveness, in the absence of bronchial wall remodeling. (PMID:18757304)
• NF2 is rendered inactive by phosphorylation of Ser 518 and this can be explained at least in part by an increased expression of CPI-17. (PMID:18835652)
• cAMP/PKA regulates the endothelial barrier via inhibition of the contractile machinery, mainly by the activation of MLCP via inhibition of CPI-17 and RhoA/Rock. (PMID:20202976)
• RACK1 may play a role in PKC/CPI-17 signaling pathway. (PMID:20875397)
• a novel signaling cascade that links RhoA-mediated calcium sensitivity to MEF2-dependent myocardin expression in VSMCs through a mechanism involving p38 MAPK, PP1alpha, and CPI-17. (PMID:22275376)
• The study characterized the CPI-17 promoter and identified binding sites for GATA-6 and nuclear factor kappa B (NF-kappaB). (PMID:23275439)
• The N-terminal 21-residue tail domain of CPI-17 is necessary for nuclear localization. Phospho-mimetic Asp-substitution of CPI-17 at Ser12 attenuates the nuclear import. (PMID:23541585)
• analysis of the interaction between plakoglobin and CPI-17, which is affected by the phosphorylation status of CPI-17 in human lung microvascular endothelial cells (PMID:23583905)
• CPI-17 has a role in restoring skin homoeostasis in cutaneous field of cancerization lesions (PMID:23800065)
• Study finds that CPI-17 (PPP1R14A protein phosphatase 1 regulatory inhibitor subunit 14A, 17 kDa) is not expressed in the healthy peripheral nervous system or in nontumour pathologies of the peripheral nervous system. CPI-17 up-regulation, however, is observed in over 90% of schwannomas, but not in neurofibroma and only rarely in malignant peripheral nerve sheath tumour. (PMID:27248983)
• CPI-17 drives Ras activity and tumorigenesis in melanomas in a two-fold way; inactivation of the tumor suppressor merlin and activation of the growth promoting ERM family. (PMID:27793041)
• The authors call the mutual sequestration mechanism through which pCPI-17 and myosin light-chain phosphatase interact inhibition by unfair competition: myosin light-chain phosphatase protects pCPI-17 from other phosphatases, while pCPI-17 blocks other substrates from the active site of myosin light-chain phosphatase. (PMID:28387646)
• The down-regulated expression of CPI-17 phosphorylated proteins might be one of the important factors of uterine atony-induced postpartum hemorrhage. (PMID:30428734)
• CPI-17 Overexpression and Its Correlation With the NF2 Mutation Spectrum in Sporadic Vestibular Schwannomas. (PMID:31789805)
• Novel role of prostate cancer risk variant rs7247241 on PPP1R14A isoform transition through allelic TF binding and CpG methylation. (PMID:34849858)
• Phosphorylated CPI-17 and MLC2 as Biomarkers of Coronary Artery Spasm-Induced Sudden Cardiac Death. (PMID:38474189)
• PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing. (PMID:38887993)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp1r14aa	ENSDARG00000011239
danio_rerio	ppp1r14ab	ENSDARG00000017710
mus_musculus	Ppp1r14a	ENSMUSG00000037166
rattus_norvegicus	Ppp1r14a	ENSRNOG00000020676
drosophila_melanogaster	CG17124	FBGN0032297
caenorhabditis_elegans		WBGENE00010109

Paralogs (3): PPP1R14D (ENSG00000166143), PPP1R14B (ENSG00000173457), PPP1R14C (ENSG00000198729)

Protein

Protein identifiers

Protein phosphatase 1 regulatory subunit 14A — Q96A00 (reviewed: Q96A00)

Alternative names: 17 kDa PKC-potentiated inhibitory protein of PP1, Protein kinase C-potentiated inhibitor protein of 17 kDa

All UniProt accessions (4): A0A0B4J2A3, Q96A00, K7EJB8, K7EMN0

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitor of PPP1CA. Has over 1000-fold higher inhibitory activity when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction.

Subcellular location. Cytoplasm.

Tissue specificity. Isoform 1 is detected in aorta and testis. Isoform 2 is detected in aorta.

Similarity. Belongs to the PP1 inhibitor family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96A00-1	1, CPI-17alpha	yes
Q96A00-2	2, CPI-17beta

RefSeq proteins (2): NP_001230876, NP_150281* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008025	CPI-17	Family
IPR036658	CPI-17_sf	Homologous_superfamily

Pfam: PF05361

UniProt features (13 total): modified residue 5, region of interest 3, compositionally biased region 2, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96A00-F1	60.69	0.00

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 (5): 136, 26, 38, 128, 134

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5625740	RHO GTPases activate PKNs

MSigDB gene sets: 133 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, SHEPARD_CRASH_AND_BURN_MUTANT_UP, KYNG_DNA_DAMAGE_DN, CHANDRAN_METASTASIS_DN, KOYAMA_SEMA3B_TARGETS_UP, ZHAN_MULTIPLE_MYELOMA_LB_UP, HAMAI_APOPTOSIS_VIA_TRAIL_DN, RIGGI_EWING_SARCOMA_PROGENITOR_UP, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_DN, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_8D_UP, GOMF_PHOSPHATASE_INHIBITOR_ACTIVITY, GOMF_PROTEIN_SERINE_THREONINE_PHOSPHATASE_INHIBITOR_ACTIVITY, GOMF_ENZYME_INHIBITOR_ACTIVITY, ZHOU_INFLAMMATORY_RESPONSE_LIVE_UP, GOMF_ENZYME_REGULATOR_ACTIVITY

GO Biological Process (2): cellular response to xenobiotic stimulus (GO:0071466), regulation of phosphorylation (GO:0042325)

GO Molecular Function (2): protein serine/threonine phosphatase inhibitor activity (GO:0004865), protein phosphatase inhibitor activity (GO:0004864)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase Effectors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
phosphorylation	1
regulation of metabolic process	1
protein serine/threonine phosphatase activity	1
protein phosphatase inhibitor activity	1
phosphoprotein phosphatase activity	1
phosphatase inhibitor activity	1
protein phosphatase regulator activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP1R14A	PPP1R12A	O14974	970
PPP1R14A	PPP1CB	P37140	871
PPP1R14A	PPP1R14D	Q9NXH3	859
PPP1R14A	C19orf33	Q9GZP8	770
PPP1R14A	PPP1CC	P36873	739
PPP1R14A	NF2	P35240	707
PPP1R14A	SPINT2	O43291	658
PPP1R14A	MYL12B	O14950	639
PPP1R14A	RHOA	P06749	631
PPP1R14A	MYLK3	Q32MK0	609
PPP1R14A	MYL9	P24844	593
PPP1R14A	HGS	O14964	588
PPP1R14A	EIF3C	Q99613	584
PPP1R14A	DAPK3	O43293	571
PPP1R14A	CALM1	P02593	570

IntAct

6 interactions, top by confidence:

A	B	Type	Score
PPP1R14A	CSNK1A1	psi-mi:“MI:0915”(physical association)	0.490
CSNK1A1	PPP1R14A	psi-mi:“MI:0915”(physical association)	0.490
PPP1R14A	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.440
PPP1R14A	PRMT5	psi-mi:“MI:0914”(association)	0.350
PRNP	PPP1R14A	psi-mi:“MI:0407”(direct interaction)	0.000

BioGRID (64): PPP1R14A (Reconstituted Complex), PPP1R14A (Co-purification), PPP1R14A (Affinity Capture-RNA), RIOK1 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), WDR77 (Affinity Capture-MS), PPP1R14A (Affinity Capture-MS), PPP1R14A (PCA), PPP1R14C (Cross-Linking-MS (XL-MS)), PPP1R14A (Cross-Linking-MS (XL-MS)), PPP1R14A (Cross-Linking-MS (XL-MS)), PPP1R14A (Proximity Label-MS), PPP1R14A (Proximity Label-MS), PPP1R14A (Proximity Label-MS), PPP1R14A (Proximity Label-MS)

ESM2 similar proteins: A1A4V9, A4D2P6, E1BDF2, F5GYI3, O18734, O35141, O43566, P0CG25, P49796, P85299, Q0II70, Q0IIA6, Q0QWG9, Q0X0E2, Q2T9R2, Q3TVI4, Q3ZBN4, Q5BJM5, Q5EBH1, Q5EBM0, Q5SNT2, Q69Z89, Q6DVA0, Q86UD0, Q8BNN1, Q8C0R7, Q8CC12, Q8CEG5, Q8IUW3, Q8IWY9, Q8N6L0, Q8VCR9, Q8WWW0, Q91VC7, Q96A00, Q96MH2, Q96P71, Q99MC0, Q9BUN5, Q9CXX9

Diamond homologs: O18734, Q62084, Q7TT52, Q8K3F3, Q8K3F4, Q8MIK9, Q8R4R9, Q8R4S0, Q8TAE6, Q91VC7, Q96A00, Q96C90, Q99MC0, Q9NXH3

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
PRKD1	“up-regulates activity”	PPP1R14A	phosphorylation
PRKCE	“up-regulates activity”	PPP1R14A	phosphorylation
PRKCA	“up-regulates activity”	PPP1R14A	phosphorylation
PRKCZ	“up-regulates activity”	PPP1R14A	phosphorylation
TP53BP2	down-regulates	PPP1R14A	binding
ILK	“up-regulates activity”	PPP1R14A	phosphorylation
ROCK2	“up-regulates activity”	PPP1R14A	phosphorylation
PPP1R14A	“down-regulates activity”	PPP1CB	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

373 predictions. Top by Δscore:

Variant	Effect	Δscore
19:38252353:C:CT	acceptor_gain	1.0000
19:38252354:A:T	acceptor_gain	1.0000
19:38252891:TACC:T	donor_loss	1.0000
19:38252972:CTC:C	acceptor_gain	1.0000
19:38252973:TCCTA:T	acceptor_loss	1.0000
19:38252975:CT:C	acceptor_loss	1.0000
19:38252982:C:CT	acceptor_gain	1.0000
19:38256134:CTCAC:C	donor_loss	1.0000
19:38256135:TCA:T	donor_loss	1.0000
19:38256137:A:AC	donor_gain	1.0000
19:38256137:ACCAT:A	donor_loss	1.0000
19:38256138:C:CA	donor_loss	1.0000
19:38256138:C:CC	donor_gain	1.0000
19:38256138:CCATG:C	donor_gain	1.0000
19:38252335:GTCC:G	acceptor_gain	0.9900
19:38252336:TCC:T	acceptor_gain	0.9900
19:38252337:CC:C	acceptor_gain	0.9900
19:38252337:CCC:C	acceptor_gain	0.9900
19:38252337:CCCTA:C	acceptor_loss	0.9900
19:38252338:CC:C	acceptor_gain	0.9900
19:38252339:C:CC	acceptor_gain	0.9900
19:38252339:C:T	acceptor_gain	0.9900
19:38252339:CTAAA:C	acceptor_loss	0.9900
19:38252349:C:CT	acceptor_gain	0.9900
19:38252349:C:T	acceptor_gain	0.9900
19:38252350:A:T	acceptor_gain	0.9900
19:38252353:C:T	acceptor_gain	0.9900
19:38252892:A:AC	donor_gain	0.9900
19:38252893:C:CC	donor_gain	0.9900
19:38252975:C:CC	acceptor_gain	0.9900

AlphaMissense

941 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:38256219:A:G	Y41H	0.998
19:38256218:T:C	Y41C	0.997
19:38252937:A:G	L80S	0.996
19:38256175:C:A	W55C	0.996
19:38256175:C:G	W55C	0.996
19:38256177:A:G	W55R	0.996
19:38256177:A:T	W55R	0.996
19:38256191:A:G	L50P	0.996
19:38256203:A:G	L46P	0.995
19:38256182:T:A	E53V	0.994
19:38256181:C:A	E53D	0.993
19:38256181:C:G	E53D	0.993
19:38256227:G:A	T38I	0.993
19:38252943:T:A	D78V	0.992
19:38256218:T:G	Y41S	0.992
19:38256219:A:C	Y41D	0.992
19:38256227:G:T	T38N	0.992
19:38256194:C:G	R49P	0.991
19:38256220:C:A	K40N	0.991
19:38256220:C:G	K40N	0.991
19:38251430:A:G	L111P	0.989
19:38252943:T:G	D78A	0.989
19:38252946:A:T	I77N	0.989
19:38256224:A:T	V39D	0.989
19:38256161:A:G	L60P	0.988
19:38256182:T:G	E53A	0.988
19:38256183:C:T	E53K	0.987
19:38256195:G:C	R49G	0.987
19:38256197:C:G	R48P	0.987
19:38256219:A:T	Y41N	0.987

dbSNP variants (sampled 300 via entrez): RS1000000675 (19:38256784 T>A), RS1000664625 (19:38255689 G>A,C), RS1001005134 (19:38255434 T>A), RS1001126044 (19:38251099 G>A), RS1001187576 (19:38256238 G>A,C), RS1001205883 (19:38255387 A>C,G), RS1001805803 (19:38256670 T>C,G), RS1003136543 (19:38254011 T>C,G), RS1003199768 (19:38253394 C>T), RS1003235036 (19:38253693 G>T), RS1004176131 (19:38252177 G>A), RS1004534438 (19:38255557 G>A), RS1004711638 (19:38258317 C>G,T), RS1004970590 (19:38255968 T>C), RS1005950278 (19:38254277 G>A,C)

Disease associations

OMIM: gene MIM:608153 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006479_109	Diverticular disease	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	6
trichostatin A	increases expression	3
entinostat	increases expression, affects cotreatment	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
FR900359	decreases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
perfluorobutanesulfonic acid	decreases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Bleomycin	decreases expression	1
Carbamazepine	affects expression	1
Estradiol	affects cotreatment, decreases expression	1
Mustard Gas	increases expression	1
Nickel	decreases expression	1
Progesterone	affects cotreatment, decreases expression	1
Thimerosal	decreases expression	1
Tretinoin	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TF62	HAP1 PPP1R14A (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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