ARPP19

Summary

ARPP19 (cAMP regulated phosphoprotein 19, HGNC:16967) is a protein-coding gene on chromosome 15q21.2, encoding cAMP-regulated phosphoprotein 19 (P56211). Protein phosphatase inhibitor that specifically inhibits protein phosphatase 2A (PP2A) during mitosis. It is a selective cancer dependency (DepMap: 10.8% of cell lines).

The 19-kD cAMP-regulated phosphoprotein plays a role in regulating mitosis by inhibiting protein phosphatase-2A (PP2A; see MIM 176915) (summary by Gharbi-Ayachi et al., 2010 [PubMed 21164014]).

Source: NCBI Gene 10776 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 17 total — 1 pathogenic, 1 likely-pathogenic
• Cancer dependency (DepMap): dependent in 10.8% of screened cell lines
• MANE Select transcript: NM_006628

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16967
Approved symbol	ARPP19
Name	cAMP regulated phosphoprotein 19
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Aliases	ARPP-19, ARPP-16, ARPP16, ENSAL
Ensembl gene	ENSG00000128989
Ensembl biotype	protein_coding
OMIM	605487
Entrez	10776

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 17 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000249822, ENST00000561650, ENST00000561971, ENST00000563277, ENST00000563566, ENST00000564163, ENST00000565288, ENST00000566423, ENST00000567669, ENST00000567830, ENST00000568196, ENST00000569281, ENST00000569723, ENST00000869288, ENST00000869289, ENST00000958249, ENST00000958250, ENST00000958251

RefSeq mRNA: 5 — MANE Select: NM_006628 NM_001306191, NM_001306195, NM_001306196, NM_001330309, NM_006628

CCDS: CCDS32242, CCDS76757, CCDS81883

Canonical transcript exons

ENST00000249822 — 3 exons

Exon	Start	End
ENSE00002581678	52568848	52569030
ENSE00002626618	52547045	52552104
ENSE00003598909	52557100	52557222

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 83.2009 / max 3975.9512, expressed in 1821 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150023	45.9790	1810
150024	16.3248	1762
150018	13.6473	150
150026	2.7801	1228
150021	1.7860	944
150025	0.9831	578
150022	0.7491	420
150019	0.6500	59
207523	0.2067	56
207522	0.0948	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	99.37	gold quality
lateral globus pallidus	UBERON:0002476	99.36	gold quality
nucleus accumbens	UBERON:0001882	99.30	gold quality
putamen	UBERON:0001874	99.29	gold quality
caudate nucleus	UBERON:0001873	99.28	gold quality
cranial nerve II	UBERON:0000941	99.26	gold quality
middle frontal gyrus	UBERON:0002702	99.08	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.06	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.01	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.83	gold quality
frontal cortex	UBERON:0001870	98.82	gold quality
frontal pole	UBERON:0002795	98.82	gold quality
frontal lobe	UBERON:0016525	98.82	gold quality
superior frontal gyrus	UBERON:0002661	98.78	gold quality
telencephalon	UBERON:0001893	98.74	gold quality
neocortex	UBERON:0001950	98.71	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.66	gold quality
sperm	CL:0000019	98.62	gold quality
entorhinal cortex	UBERON:0002728	98.61	gold quality
orbitofrontal cortex	UBERON:0004167	98.61	gold quality
cerebral cortex	UBERON:0000956	98.59	gold quality
cingulate cortex	UBERON:0003027	98.58	gold quality
anterior cingulate cortex	UBERON:0009835	98.56	gold quality
temporal lobe	UBERON:0001871	98.48	gold quality
postcentral gyrus	UBERON:0002581	98.45	gold quality
parietal lobe	UBERON:0001872	98.43	gold quality
corpus callosum	UBERON:0002336	98.43	gold quality
amygdala	UBERON:0001876	98.39	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.39	gold quality
biceps brachii	UBERON:0001507	98.33	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	45.94
E-HCAD-30	no	818.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

288 targeting ARPP19, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4668-3P	100.00	68.74	2635
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-12118	100.00	65.88	1270
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-373-5P	99.98	75.36	4753

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• Decreased levels of ARPP-19 and PKA in brains of Down syndrome and Alzheimer’s disease. (PMID:11771749)
• ARPP19 gene expression is decreased in follicular variant of papillary thyroid carcinoma. (PMID:21509594)
• ARPP-19 may play a role in HCC pathogenesis through regulating cell proliferation. (PMID:25547487)
• Data show that micrRNA miR-320a directly targets cAMP-regulated phosphoprotein 19 (ARPP-19) and estrogen-related receptor gamma protein (ERRgamma) in breast cancer cell lines. (PMID:25736597)
• Study showed that ARPP-19 promoted both proliferation and metastasis of human glioma cells and the expression of ARPP-19 and CD147 in high-grade glioma was significantly higher than that in the low-grade glioma. (PMID:27380244)
• Together, the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition. (PMID:28613156)
• The cAMP-regulated phosphoprotein 19 (ARPP19) was a direct target of miR-802 and could reverse the inhibitory function of miR-802. These data suggest that the IGFL2-AS1/miR-802/ARPP19 axis plays a critical role in the progression and metastasis of gastric cancer. (PMID:31943339)
• Long Noncoding RNA DLX6-AS1 Promotes the Progression in Cervical Cancer by Targeting miR-16-5p/ARPP19 Axis. (PMID:32077747)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	arpp19a	ENSDARG00000032532
danio_rerio	arpp19b	ENSDARG00000039880
mus_musculus	Arpp19	ENSMUSG00000007656
rattus_norvegicus	LOC100360828	ENSRNOG00000023086
rattus_norvegicus	Arpp19	ENSRNOG00000063103
caenorhabditis_elegans	ensa-1	WBGENE00010730

Paralogs (1): ENSA (ENSG00000143420)

Protein

Protein identifiers

cAMP-regulated phosphoprotein 19 — P56211 (reviewed: P56211)

All UniProt accessions (4): P56211, H3BMD8, H3BQ52, H3BTD3

UniProt curated annotations — full annotation on UniProt →

Function. Protein phosphatase inhibitor that specifically inhibits protein phosphatase 2A (PP2A) during mitosis. Inhibition of PP2A is enhanced when ARPP19 is phosphorylated. When phosphorylated at Ser-62 during mitosis, specifically interacts with PPP2R2D (PR55-delta) and inhibits its activity, leading to inactivation of PP2A, an essential condition to keep cyclin-B1-CDK1 activity high during M phase. May indirectly enhance GAP-43 expression.

Subunit / interactions. Interacts (when phosphorylated at Ser-62) with PPP2R2D. Interacts with SNCA. Interacts with PPP2R2A; the interaction is direct and this interaction inhibits PP2A activity.

Subcellular location. Cytoplasm.

Post-translational modifications. Phosphorylation at Ser-62 by MASTL/GWL during mitosis is essential for interaction with PPP2R2D (PR55-delta) and subsequent inactivation of PP2A. Phosphorylated by PKA.

Induction. Expression may be regulated by miR-451.

Similarity. Belongs to the endosulfine family.

Isoforms (2)

UniProt ID	Names	Canonical?
P56211-1	ARPP-19	yes
P56211-2	ARPP-16

RefSeq proteins (5): NP_001293120, NP_001293124, NP_001293125, NP_001317238, NP_006619* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006760	Endosulphine	Family

Pfam: PF04667

UniProt features (19 total): modified residue 8, helix 2, turn 2, region of interest 2, compositionally biased region 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8TTB	ELECTRON MICROSCOPY	2.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56211-F1	69.19	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.

Post-translational modifications (8): 104, 104, 109, 1, 2, 2, 23, 62

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2465910	MASTL Facilitates Mitotic Progression
R-HSA-1640170	Cell Cycle
R-HSA-68875	Mitotic Prophase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic

MSigDB gene sets: 300 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_CARBOHYDRATE_TRANSPORT, GCM_PTPRD, GOBP_CELL_CYCLE_PHASE_TRANSITION, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_DN, TACAATC_MIR508, CTATGCA_MIR153, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MARTINEZ_RB1_TARGETS_UP, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_REGULATION_OF_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_MONOSACCHARIDE_BIOSYNTHETIC_PROCESS, GROSS_HYPOXIA_VIA_ELK3_UP

GO Biological Process (5): G2/M transition of mitotic cell cycle (GO:0000086), mitotic cell cycle (GO:0000278), positive regulation of gluconeogenesis (GO:0045722), positive regulation of D-glucose import across plasma membrane (GO:0046326), cell division (GO:0051301)

GO Molecular Function (7): protein phosphatase inhibitor activity (GO:0004864), signaling receptor binding (GO:0005102), potassium channel regulator activity (GO:0015459), phosphatase inhibitor activity (GO:0019212), protein phosphatase regulator activity (GO:0019888), protein phosphatase 2A binding (GO:0051721), protein binding (GO:0005515)

GO Cellular Component (2): nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Mitotic Prophase	1
M Phase	1
Cell Cycle, Mitotic	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoprotein phosphatase activity	2
phosphatase regulator activity	2
protein phosphatase binding	2
cellular anatomical structure	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
cell cycle	1
mitotic nuclear division	1
gluconeogenesis	1
regulation of gluconeogenesis	1
positive regulation of biosynthetic process	1
positive regulation of glucose metabolic process	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
cellular process	1
phosphatase inhibitor activity	1
protein phosphatase regulator activity	1
protein binding	1
potassium channel activity	1
ion channel regulator activity	1
enzyme inhibitor activity	1
phosphatase activity	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

942 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARPP19	MASTL	Q96GX5	979
ARPP19	PPP2R2D	Q66LE6	970
ARPP19	MINK1	Q8N4C8	916
ARPP19	ARPP21	Q9UBL0	890
ARPP19	PPP1R1B	Q9UD71	799
ARPP19	CDK1	P06493	778
ARPP19	PPP2R1A	P30153	659
ARPP19	PPP2R2A	P50409	647
ARPP19	MAST3	O60307	604
ARPP19	PPP2CA	P05323	593
ARPP19	SGO1	Q5FBB7	546
ARPP19	SGO2	Q562F6	530
ARPP19	REC8	O95072	514
ARPP19	WEE1	P30291	502
ARPP19	EEF2	P13639	487

IntAct

36 interactions, top by confidence:

A	B	Type	Score
PPP2R2A	PPP2R1A	psi-mi:“MI:0915”(physical association)	0.970
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	ARPP19	psi-mi:“MI:0915”(physical association)	0.750
PPP2R2A	ARPP19	psi-mi:“MI:0407”(direct interaction)	0.630
ARPP19	PPP2R2A	psi-mi:“MI:0914”(association)	0.630
PPP2R2A	ARPP19	psi-mi:“MI:0915”(physical association)	0.630
ARPP19	SPDYC	psi-mi:“MI:0915”(physical association)	0.560
APP	ARPP19	psi-mi:“MI:0915”(physical association)	0.560
PPP2R1A	ENSA	psi-mi:“MI:0914”(association)	0.530
	ARPP19	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
PPP2R2D	MAST4	psi-mi:“MI:0914”(association)	0.350
	ENO2	psi-mi:“MI:0914”(association)	0.350
MAPT	PITPNM1	psi-mi:“MI:2364”(proximity)	0.270
MAPT	DCTN6	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (32): ARPP19 (Co-fractionation), ARPP19 (Co-fractionation), ARPP19 (Co-fractionation), ARPP19 (Affinity Capture-RNA), SPDYC (Two-hybrid), ARPP19 (Affinity Capture-MS), ARPP19 (Co-fractionation), ARPP19 (Co-fractionation), RC3H1 (Co-fractionation), CHID1 (Co-fractionation), ARPP19 (Affinity Capture-MS), ARPP19 (Proximity Label-MS), ARPP19 (Proximity Label-MS), ARPP19 (Proximity Label-MS), ENSA (Negative Genetic)

ESM2 similar proteins: A2AQ19, B5G1C4, B5XE27, O43395, O43768, O75391, O95983, P19237, P56211, P56212, P60840, P60841, P68210, P68211, Q0MUU2, Q13123, Q13435, Q1L8X2, Q28055, Q28GU6, Q2KI76, Q2KIA6, Q3UJB0, Q3ZBD4, Q5NVI3, Q5R5F1, Q5R5J3, Q5RAD5, Q5RB90, Q5ZIF8, Q5ZJ85, Q5ZLY8, Q66HG8, Q6DEB4, Q6GQG3, Q6NVR1, Q712U5, Q712U6, Q7TNE3, Q7ZXH9

Diamond homologs: B5G1C4, B5XE27, O43768, P56211, P56212, P60840, P60841, P68210, P68211, P79058, Q1L8X2, Q28055, Q28GU6, Q5ZIF8, Q5ZLY8, Q6DEB4, Q6GQG3, Q6NVR1, Q712U5, Q712U6, Q7ZXH9, P53897, Q9P305

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MASTL	“up-regulates activity”	ARPP19	phosphorylation
ARPP19	“down-regulates activity”	PPP2R2D	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	10
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
147481	GRCh38/hg38 15q21.2-21.3(chr15:51276690-57088386)x1	Pathogenic
980039	GRCh37/hg19 15q21.2-21.3(chr15:51792729-55134365)x1	Likely pathogenic

SpliceAI

767 predictions. Top by Δscore:

Variant	Effect	Δscore
15:52551907:G:C	donor_gain	1.0000
15:52551969:T:TA	donor_gain	1.0000
15:52552100:TTTTG:T	acceptor_gain	1.0000
15:52552101:TTTG:T	acceptor_gain	1.0000
15:52552103:TG:T	acceptor_gain	1.0000
15:52552105:C:CC	acceptor_gain	1.0000
15:52569114:A:AC	donor_gain	1.0000
15:52569115:C:CC	donor_gain	1.0000
15:52569154:T:TA	donor_gain	1.0000
15:52551924:AG:A	donor_gain	0.9900
15:52552102:TTG:T	acceptor_gain	0.9900
15:52552103:TGCT:T	acceptor_loss	0.9900
15:52552105:C:CA	acceptor_loss	0.9900
15:52552107:A:C	acceptor_gain	0.9900
15:52557093:AACTT:A	donor_loss	0.9900
15:52557094:ACTT:A	donor_loss	0.9900
15:52557095:CTT:C	donor_loss	0.9900
15:52557096:TTA:T	donor_loss	0.9900
15:52557097:TACC:T	donor_loss	0.9900
15:52557098:AC:A	donor_gain	0.9900
15:52557098:ACC:A	donor_gain	0.9900
15:52557098:ACCCC:A	donor_loss	0.9900
15:52557099:C:CA	donor_loss	0.9900
15:52557099:CC:C	donor_gain	0.9900
15:52557099:CCC:C	donor_gain	0.9900
15:52568843:CTCA:C	donor_loss	0.9900
15:52568844:TCA:T	donor_loss	0.9900
15:52568845:CACCT:C	donor_loss	0.9900
15:52568846:ACC:A	donor_loss	0.9900
15:52568847:CCTT:C	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000156086 (15:52563784 A>T), RS1000253271 (15:52547312 T>C), RS1000266096 (15:52558174 G>A), RS1000318232 (15:52569082 C>A), RS1000438929 (15:52563625 T>C,G), RS1000535345 (15:52557564 ATATT>A), RS1000667169 (15:52569266 T>C), RS1000710457 (15:52546750 G>T), RS1000722304 (15:52558405 A>T), RS1000908010 (15:52563522 T>C), RS1001033626 (15:52551349 A>G), RS1001537933 (15:52554467 T>C,G), RS1001560955 (15:52563246 T>A,C), RS1001945567 (15:52568711 C>A,G), RS1002055020 (15:52557767 A>G)

Disease associations

OMIM: gene MIM:605487 | 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
GCST006585_870	Blood protein levels	5.000000e-06

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
sodium arsenite	decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
tetrahydropalmatine	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
ferrous chloride	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
azoxystrobin	increases expression	1
ICG 001	decreases expression	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Dasatinib	decreases reaction, increases expression, affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	affects cotreatment, decreases expression, decreases reaction, increases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases expression	1
Aspirin	increases expression	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Gasoline	increases expression, affects cotreatment, increases abundance	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2S8	Abcam HEK293T ARPP19 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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