ACTR3

Summary

ACTR3 (actin related protein 3, HGNC:170) is a protein-coding gene on chromosome 2q14.1, encoding Actin-related protein 3 (P61158). ATP-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). It is a selective cancer dependency (DepMap: 41.6% of cell lines).

The specific function of this gene has not yet been determined; however, the protein it encodes is known to be a major constituent of the ARP2/3 complex. This complex is located at the cell surface and is essential to cell shape and motility through lamellipodial actin assembly and protrusion. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 10096 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 44 total — 1 pathogenic
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 41.6% of screened cell lines
• MANE Select transcript: NM_005721

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:170
Approved symbol	ACTR3
Name	actin related protein 3
Location	2q14.1
Locus type	gene with protein product
Status	Approved
Aliases	ARP3
Ensembl gene	ENSG00000115091
Ensembl biotype	protein_coding
OMIM	604222
Entrez	10096

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 21 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000263238, ENST00000415792, ENST00000443297, ENST00000446821, ENST00000478928, ENST00000484165, ENST00000489779, ENST00000535589, ENST00000868069, ENST00000868070, ENST00000868071, ENST00000868072, ENST00000868073, ENST00000868074, ENST00000868075, ENST00000868076, ENST00000868077, ENST00000868078, ENST00000868079, ENST00000931225, ENST00000931226, ENST00000958925, ENST00000958926, ENST00000958927, ENST00000958928

RefSeq mRNA: 2 — MANE Select: NM_005721 NM_001277140, NM_005721

CCDS: CCDS33277, CCDS63000

Canonical transcript exons

ENST00000263238 — 12 exons

Exon	Start	End
ENSE00000774339	113942186	113942359
ENSE00001009530	113951720	113951845
ENSE00001009533	113955623	113955706
ENSE00001009534	113951479	113951571
ENSE00001362124	113890089	113890323
ENSE00001919848	113957360	113962596
ENSE00003490315	113916884	113917008
ENSE00003502000	113913172	113913227
ENSE00003530284	113931301	113931396
ENSE00003544362	113939959	113940102
ENSE00003668750	113934279	113934386
ENSE00003736915	113927345	113927455

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 234.0515 / max 3235.3302, expressed in 1828 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22163	227.4136	1828
22162	3.9892	1348
22169	1.1118	392
22164	0.8788	469
22167	0.3601	79
22165	0.2083	78
22166	0.0897	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	99.73	gold quality
squamous epithelium	UBERON:0006914	99.60	gold quality
endothelial cell	CL:0000115	99.58	gold quality
tongue squamous epithelium	UBERON:0006919	99.57	gold quality
sperm	CL:0000019	99.55	gold quality
epithelium of esophagus	UBERON:0001976	99.51	gold quality
trabecular bone tissue	UBERON:0002483	99.47	gold quality
cervix squamous epithelium	UBERON:0006922	99.47	gold quality
epithelium of nasopharynx	UBERON:0001951	99.43	gold quality
nasopharynx	UBERON:0001728	99.41	gold quality
male germ cell	CL:0000015	99.37	gold quality
gingiva	UBERON:0001828	99.32	gold quality
gingival epithelium	UBERON:0001949	99.32	gold quality
secondary oocyte	CL:0000655	99.27	gold quality
oral cavity	UBERON:0000167	99.26	gold quality
vermiform appendix	UBERON:0001154	99.21	gold quality
amniotic fluid	UBERON:0000173	99.16	gold quality
upper leg skin	UBERON:0004262	99.14	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.10	gold quality
caecum	UBERON:0001153	99.08	gold quality
visceral pleura	UBERON:0002401	99.07	gold quality
cervix epithelium	UBERON:0004801	99.06	gold quality
pleura	UBERON:0000977	99.03	gold quality
parietal pleura	UBERON:0002400	99.03	gold quality
cauda epididymis	UBERON:0004360	99.02	gold quality
monocyte	CL:0000576	98.98	gold quality
mononuclear cell	CL:0000842	98.98	gold quality
colonic mucosa	UBERON:0000317	98.97	gold quality
jejunal mucosa	UBERON:0000399	98.97	gold quality
lymph node	UBERON:0000029	98.96	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	20.60
E-CURD-46	yes	20.07
E-MTAB-10042	yes	8.25
E-CURD-88	no	3.64
E-CURD-112	no	3.32
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, ZNF331

miRNA regulators (miRDB)

152 targeting ACTR3, 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-340-5P	100.00	72.50	4437
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-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548J-3P	99.94	72.61	4881

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 41.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Arp2/3 complex is required for actin polymerization during platelet shape change. (PMID:12036877)
• Platelets activate Arp2/3 complex, assemble actin, and change shape in the absence of WASp, indicating a more specialized role for WASp in these cells. (PMID:12200375)
• Results suggest that recruitment of factors by Wiskott-Aldrich Syndrome protein (WASP) and Scar1 stimulates cellular actin-based motility and actin nucleation with the Arp2/3 complex. (PMID:12429845)
• Arp2/3 complex contribution to actin filament nucleation in platelets and fibroblasts importantly requires free barbed ends generated by severing and uncapping. (PMID:12464680)
• cortactin links receptor endocytosis to actin polymerization by binding both CD2AP and the Arp2/3 complex, which may facilitate the trafficking of internalized growth factor receptors (PMID:12672817)
• ARP3-mediated actin polymerization is regulated by phosphorylation of the WASP protein. (PMID:12791263)
• The interaction between cortactin and Arp2/3 complex plays an important role in S1P-mediated remodeling of endothelial cells. (PMID:15242766)
• Arp2/3 complex genes have roles in actin organization and possibly in cancer phenotypes (PMID:15279900)
• existence of an Arp2/3 complex-dependent event during the early phase of the life cycles of both primate lentiviruses and intracellular mature vaccinia virus (PMID:15385624)
• signalling pathways leading to Arp2/3-dependent actin nucleation play an important role in Salmonella typhimurium invasion, but are not involved in intracellular Salmonella-induced actin assembly (PMID:15469433)
• T-plastin increases Arp2/3-mediated actin-based movement (PMID:15741236)
• These results indicate that interaction between the Arp2/3 complex and WASP stimulates actin polymerization and integrin beta-1-mediated adhesion during MCP-1-induced chemotaxis of THP-1 cells. (PMID:16004967)
• the binding of the C terminus of SPIN90 with both the Arp2/3 complex (actin-related proteins Arp 2 and Arp 3) and G-actin activates the former, leading to actin polymerization (PMID:16253999)
• in activation of the Arp2/3 complex, the C domain first primes the complex by inducing a necessary conformational change and then initiates nucleus assembly by bringing an actin monomer into proximity of the primed complex (PMID:16403731)
• signal-induced relief of the autoinhibited fold of IQGAP1 allows activation of N-WASP to stimulate Arp2/3-dependent actin assembly (PMID:17085436)
• Data show that Chlamydia trachomatis activates Rac and promotes its interaction with WAVE2 and Abi-1 to activate the Arp2/3 complex resulting in the induction of actin cytoskeletal rearrangements that are required for invasion. (PMID:17501982)
• Taken together, our data suggest that Apr3 should play an important role in ATRA signal pathway. (PMID:17524364)
• p120 depletion led to dramatic loss of cortactin and its partner, Arp3, from the cell leading edges (PMID:17576929)
• Results suggest that WAVE and the Arp2/3 complex jointly orchestrate different types of actin-based plasma membrane protrusions by promoting ruffling and inhibiting mDia2-induced filopodia. (PMID:18516090)
• the exchange rate of N-WASP controls the rate of ARP2/3-complex-dependent actin-based motility by regulating the extent of actin polymerization by antagonizing filament capping (PMID:19262673)
• The Arp2/3 complex, an actin-nucleating factor, is recruited at the ring structure and is important for parasite entry. (PMID:19286135)
• Loss of Arp2/3 function led to defects in cell adhesion and actin assembly at the junction with the target cell (the lytic synapse) (PMID:19913427)
• key residues at this interface were crucial for actin nucleation and Y-branching, high-affinity F-actin binding, and Y-branch stability, demonstrating that the affinity of Arp2/3 complex for F actin independently modulates branch formation and stability. (PMID:20404198)
• The results identify Arp2/3 complex as a key factor in the generation of the dynamic actin cluster during mitosis. (PMID:20974812)
• the centrosome transiently recruits Arp2/3 to perform processes such as centrosome separation prior to mitotic entry. (PMID:21108927)
• Anthrax edema toxin induced transendothelial cell tunnels are resealed by MIM via Arp2/3-driven actin polymerization. (PMID:22100162)
• We demonstrate that WAVE2-Arp2/3 is a major nucleator of actin assembly at the zonula adherens and likely acts in response to junctional Rac signaling (PMID:23051739)
• Study suggested that positive CFL1 and Arp3 expression are closely related to tumor progression, metastasis, and poor prognosis of gallbladder cancer. (PMID:23320827)
• The Arp2/Arp3 complex has a role in osmotic signaling. (PMID:24344184)
• Cortactin has a role as a scaffold for Arp2/3 and WAVE2 at the epithelial zonula adherens (PMID:24469447)
• study unveils an ARP2/3:VCA-independent function of nuclear-WASp in TH1 gene activation that is uncoupled from its cytoplasmic role in actin polymerization. (PMID:24872192)
• The loss of the Arp2/3 complex acts as a stress that initiates cell cycle arrest by triggering p16INK4a/p14Arf transcription. (PMID:25264243)
• Platelet actin nodule formation is dependent on WASp and the ARP2/3 complex. (PMID:26028144)
• Suggest alpha5beta1/Arp2/Arp3/FHOD3 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo. (PMID:26370503)
• demonstrate that the Arp2/3 complex in higher eukaryotes is actually a family of complexes with different properties (PMID:26655834)
• RARalpha regulates Arp2/3-mediated actin cytoskeletal dynamics through a non-genomic signaling pathway (PMID:26848712)
• miR-24-1*/let-7a*-ARP2/3 complex-RAC isoforms pathway may represent a novel pathogenic mechanism for Hirschsprung disease. (PMID:26991540)
• Kv3.3 regulates Arp2/3-dependent cortical actin nucleation mediated by Hax-1; resulting cortical actin structures interact with the channel’s gating machinery to slow its inactivation rate during sustained membrane depolarizations; a mutation that leads to late-onset spinocerebellar ataxia type 13. (PMID:26997484)
• These findings indicate that inhibition of the Rac1WAVE2Arp2/3 signaling pathway may promote radiosensitivity, which may partially result from the downregulation of CFL1 in U251 human glioma cells. (PMID:27052944)
• Arp2 and Arp3 expression was increased under atherosclerotic conditions both in ApoE-/- mice and in oxidized low-density lipoproteins stimulated human coronary artery endothelial cells (HCAECs). (PMID:27181356)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Actr3	ENSMUSG00000026341
rattus_norvegicus	Actr3	ENSRNOG00000003206
drosophila_melanogaster	Arp3	FBGN0262716
caenorhabditis_elegans	arx-1	WBGENE00000199

Paralogs (26): ACTR6 (ENSG00000075089), ACTB (ENSG00000075624), ACTL6B (ENSG00000077080), ACTR5 (ENSG00000101442), ACTR3C (ENSG00000106526), ACTA2 (ENSG00000107796), ACTR8 (ENSG00000113812), ACTR1B (ENSG00000115073), ACTL8 (ENSG00000117148), ACTRT1 (ENSG00000123165), ACTR10 (ENSG00000131966), ACTR3B (ENSG00000133627), ACTL6A (ENSG00000136518), ACTR2 (ENSG00000138071), ACTR1A (ENSG00000138107), ACTA1 (ENSG00000143632), ACTL7B (ENSG00000148156), ACTC1 (ENSG00000159251), ACTG2 (ENSG00000163017), ACTBL2 (ENSG00000169067), ACTRT2 (ENSG00000169717), ACTL9 (ENSG00000181786), ACTG1 (ENSG00000184009), ACTRT3 (ENSG00000184378), ACTL7A (ENSG00000187003), ACTL10 (ENSG00000288649)

Protein

Protein identifiers

Actin-related protein 3 — P61158 (reviewed: P61158)

Alternative names: Actin-like protein 3

All UniProt accessions (5): P61158, B4DXW1, F8WDR7, F8WE84, F8WEW2

UniProt curated annotations — full annotation on UniProt →

Function. ATP-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility. Seems to contact the pointed end of the daughter actin filament. In podocytes, required for the formation of lamellipodia downstream of AVIL and PLCE1 regulation. In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA. The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs). Plays a role in ciliogenesis.

Subunit / interactions. Component of the Arp2/3 complex composed of ACTR2/ARP2, ACTR3/ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC. Interacts with WHDC1. Interacts weakly with MEFV. Interacts with AVIL.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Nucleus.

Similarity. Belongs to the actin family. ARP3 subfamily.

RefSeq proteins (2): NP_001264069, NP_005712* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004000	Actin	Family
IPR020902	Actin/actin-like_CS	Conserved_site
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00022

UniProt features (7 total): modified residue 5, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9I2B	ELECTRON MICROSCOPY	3
8P94	ELECTRON MICROSCOPY	3.3
6UHC	ELECTRON MICROSCOPY	3.9
6YW6	ELECTRON MICROSCOPY	4.2
6YW7	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61158-F1	91.64	0.82

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): 2, 240, 244, 251, 254

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-5663213	RHO GTPases Activate WASPs and WAVEs
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-199991	Membrane Trafficking
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-422475	Axon guidance
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-9658195	Leishmania infection
R-HSA-9664407	Parasite infection
R-HSA-9664417	Leishmania phagocytosis
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3
R-HSA-9824443	Parasitic Infection Pathways

MSigDB gene sets: 317 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_MSN, TSENG_IRS1_TARGETS_UP, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GNF2_BNIP2, GOBP_RESPONSE_TO_PEPTIDE, GOBP_SPINDLE_LOCALIZATION, GOBP_CHROMOSOME_LOCALIZATION, MATTIOLI_MGUS_VS_PCL, MORF_HDAC2, REACTOME_MEMBRANE_TRAFFICKING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_LAMELLIPODIUM_ASSEMBLY

GO Biological Process (13): establishment or maintenance of cell polarity (GO:0007163), asymmetric cell division (GO:0008356), positive regulation of lamellipodium assembly (GO:0010592), meiotic chromosome movement towards spindle pole (GO:0016344), meiotic cytokinesis (GO:0033206), Arp2/3 complex-mediated actin nucleation (GO:0034314), positive regulation of transcription by RNA polymerase II (GO:0045944), spindle localization (GO:0051653), cilium assembly (GO:0060271), actin polymerization-dependent cell motility (GO:0070358), cellular response to type II interferon (GO:0071346), cell projection organization (GO:0030030), meiotic cell cycle (GO:0051321)

GO Molecular Function (6): actin binding (GO:0003779), structural constituent of cytoskeleton (GO:0005200), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515), actin filament binding (GO:0051015)

GO Cellular Component (14): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), Arp2/3 protein complex (GO:0005885), brush border (GO:0005903), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), membrane (GO:0016020), lamellipodium (GO:0030027), site of double-strand break (GO:0035861), extracellular exosome (GO:0070062), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Fcgamma receptor (FCGR) dependent phagocytosis	1
EPH-Ephrin signaling	1
RHO GTPase Effectors	1
Membrane Trafficking	1
Leishmania phagocytosis	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Vesicle-mediated transport	1
Innate Immune System	1
Axon guidance	1
Nervous system development	1
Disease	1
Parasitic Infection Pathways	1
Leishmania infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
meiotic cell cycle	2
meiotic cell cycle process	2
cytoskeleton	2
cellular process	1
cell division	1
regulation of lamellipodium assembly	1
lamellipodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
positive regulation of lamellipodium organization	1
meiotic chromosome segregation	1
chromosome movement towards spindle pole	1
cytoskeleton-dependent cytokinesis	1
actin nucleation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cell cycle process	1
organelle localization	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
cell motility	1
response to type II interferon	1
cellular response to cytokine stimulus	1
cellular component organization	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
cytoskeletal protein binding	1
structural molecule activity	1
cytoskeleton organization	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

208 interactions, top by confidence:

A	B	Type	Score
ARPC1B	ARPC2	psi-mi:“MI:0915”(physical association)	0.920
ARPC1B	ARPC2	psi-mi:“MI:0914”(association)	0.920
ARPC4	ARPC1B	psi-mi:“MI:0914”(association)	0.910
ARPC1A	ARPC2	psi-mi:“MI:0914”(association)	0.900
ARPC1A	ARPC2	psi-mi:“MI:0915”(physical association)	0.900
ARPC5	ARPC1B	psi-mi:“MI:0914”(association)	0.890
ACTR3	ARPC1B	psi-mi:“MI:0914”(association)	0.890

BioGRID (505): ACTR3 (Affinity Capture-RNA), ACTR3 (Affinity Capture-MS), ACTR3 (Affinity Capture-MS), ACTR3 (Affinity Capture-MS), ACTR3 (Affinity Capture-MS), ACTR3 (Affinity Capture-MS), ACTR3 (Affinity Capture-RNA), ACTR3 (Co-fractionation), ACTR3 (Co-fractionation), ACTR3 (Co-fractionation), ACTR3 (Co-fractionation), ACTR3 (Co-fractionation), ACTR3 (Co-fractionation), ACTR3 (Co-fractionation), ACTR3 (Co-fractionation)

ESM2 similar proteins: A0A1L8EV45, C9WPN6, F1QGW6, F6RQL9, O73723, O77676, P00516, P0C605, P20461, P23258, P23330, P31321, P32392, P35250, P41091, P53033, P61157, P61158, P62482, P62483, P81795, P83887, P83888, Q05B83, Q0VCD2, Q13126, Q13303, Q13976, Q27955, Q2KHU8, Q2KJ81, Q2VIR3, Q32KM1, Q4V7C7, Q5R797, Q5R8R1, Q5ZHS1, Q5ZMS3, Q641P0, Q641W4

Diamond homologs: A0A1L8EV45, A2BDB0, A2X6S3, O16808, O17320, O18840, O73723, P02576, P02578, P04752, P04829, P07829, P0DM41, P0DM42, P10984, P10986, P10988, P10990, P12716, P13363, P17126, P17128, P22132, P26183, P27131, P30162, P30163, P32390, P32392, P35432, P41112, P41339, P42528, P43239, P45886, P47117, P53458, P53461, P53468, P53470

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ACTR3	“form complex”	ARP2/3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 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
RHO GTPases Activate WASPs and WAVEs	11	33.9×	2e-12
Parasite infection	10	33.6×	2e-11
Leishmania phagocytosis	10	33.6×	2e-11
RHO GTPases activate PAKs	6	31.7×	1e-06
Fcgamma receptor (FCGR) dependent phagocytosis	10	27.0×	2e-10
FCGR3A-mediated phagocytosis	13	23.6×	2e-12
Regulation of actin dynamics for phagocytic cup formation	13	23.2×	2e-12
EPHB-mediated forward signaling	9	23.2×	7e-09

GO biological processes:

GO term	Partners	Fold	FDR
Arp2/3 complex-mediated actin nucleation	8	67.4×	1e-10
actin polymerization or depolymerization	5	30.6×	3e-04
actin filament polymerization	5	19.3×	1e-03
platelet aggregation	5	13.5×	3e-03
cellular response to type II interferon	7	11.7×	1e-03
actin filament organization	8	7.6×	2e-03
endocytosis	9	6.9×	1e-03
actin cytoskeleton organization	10	6.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1526888	GRCh37/hg19 2q13-14.3(chr2:113188197-128144700)	Pathogenic

SpliceAI

2160 predictions. Top by Δscore:

Variant	Effect	Δscore
2:113890276:G:GT	donor_gain	1.0000
2:113890321:GGG:G	donor_gain	1.0000
2:113890322:GG:G	donor_gain	1.0000
2:113890322:GGG:G	donor_gain	1.0000
2:113890323:GG:G	donor_gain	1.0000
2:113913166:TTGCA:T	acceptor_loss	1.0000
2:113913167:TGCA:T	acceptor_loss	1.0000
2:113913168:GCA:G	acceptor_loss	1.0000
2:113913169:CAG:C	acceptor_loss	1.0000
2:113913170:A:AG	acceptor_gain	1.0000
2:113913171:G:GG	acceptor_gain	1.0000
2:113913171:G:GT	acceptor_loss	1.0000
2:113913171:GGT:G	acceptor_gain	1.0000
2:113913171:GGTAT:G	acceptor_gain	1.0000
2:113913223:TTCCT:T	donor_gain	1.0000
2:113913224:TCCT:T	donor_gain	1.0000
2:113913225:CCT:C	donor_gain	1.0000
2:113913226:CT:C	donor_gain	1.0000
2:113913227:TG:T	donor_loss	1.0000
2:113913228:G:GG	donor_gain	1.0000
2:113913228:GTA:G	donor_loss	1.0000
2:113913229:T:TG	donor_loss	1.0000
2:113913230:AAGTA:A	donor_loss	1.0000
2:113916883:G:GA	acceptor_loss	1.0000
2:113917006:AAGGT:A	donor_loss	1.0000
2:113917007:AGGTA:A	donor_loss	1.0000
2:113917009:G:A	donor_loss	1.0000
2:113917010:T:A	donor_loss	1.0000
2:113927341:ATAGT:A	acceptor_gain	1.0000
2:113927343:A:AG	acceptor_gain	1.0000

AlphaMissense

2740 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:113890317:G:A	G13D	1.000
2:113913181:A:C	K18N	1.000
2:113913181:A:T	K18N	1.000
2:113913185:G:A	G20R	1.000
2:113913185:G:C	G20R	1.000
2:113913186:G:A	G20E	1.000
2:113913207:C:A	P27Q	1.000
2:113916970:G:C	G63R	1.000
2:113916971:G:T	G63V	1.000
2:113927360:G:C	G81R	1.000
2:113927361:G:A	G81D	1.000
2:113927367:T:A	V83D	1.000
2:113927375:T:A	W86R	1.000
2:113927375:T:C	W86R	1.000
2:113927377:G:C	W86C	1.000
2:113927377:G:T	W86C	1.000
2:113931318:T:A	N118K	1.000
2:113931318:T:G	N118K	1.000
2:113931332:G:T	R123M	1.000
2:113931333:G:C	R123S	1.000
2:113931333:G:T	R123S	1.000
2:113931343:G:C	A127P	1.000
2:113931344:C:A	A127D	1.000
2:113934289:C:A	A148D	1.000
2:113934339:G:C	G165R	1.000
2:113934340:G:A	G165D	1.000
2:113934349:T:A	I168K	1.000
2:113934351:G:C	D169H	1.000
2:113934352:A:C	D169A	1.000
2:113934352:A:G	D169G	1.000

dbSNP variants (sampled 300 via entrez): RS1000004537 (2:113949321 T>C), RS1000016442 (2:113920138 G>T), RS1000079442 (2:113899896 C>T), RS1000130646 (2:113893953 A>G), RS1000143841 (2:113901106 G>A,T), RS1000211857 (2:113923641 G>A), RS1000244093 (2:113926500 T>C), RS1000283771 (2:113939265 G>A,T), RS1000376806 (2:113917543 C>G), RS1000388625 (2:113960645 A>C,G), RS1000439257 (2:113933186 A>G), RS1000444229 (2:113911371 A>G), RS1000460014 (2:113948120 C>T), RS1000492695 (2:113920466 T>C), RS1000576452 (2:113925376 A>G)

Disease associations

OMIM: gene MIM:604222 | 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
GCST002187_2	Systolic blood pressure in sickle cell anemia	2.000000e-06
GCST009391_1064	Metabolite levels	3.000000e-06
GCST009391_1584	Metabolite levels	7.000000e-06
GCST010396_107	Gut microbiota (bacterial taxa, hurdle binary method)	5.000000e-07
GCST90011898_67	Alanine aminotransferase levels	1.000000e-13
GCST90020024_888	A body shape index	5.000000e-09
GCST90020025_1552	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST90020027_94	Waist-hip index	7.000000e-09
GCST90020029_513	Waist circumference adjusted for body mass index	6.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0010364	lysophosphatidylcholine 20:5 measurement
EFO:0010349	cholesteryl ester 20:5 measurement
EFO:0007874	gut microbiome measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105857 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 11,817 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2146883	COBIMETINIB	4	9,422
CHEMBL3301622	GILTERITINIB	4	2,395

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.44	Kd	36	nM	COBIMETINIB
7.28	IC50	53	nM	COBIMETINIB
6.28	Kd	523.4	nM	CHEMBL5653589
6.28	ED50	523.4	nM	CHEMBL5653589
5.26	Kd	5511	nM	GILTERITINIB

PubChem BioAssay actives

3 with measured affinity, of 238 total; 3 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
Cobimetinib	1424899: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0360	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147799: Binding affinity to human ACTR3 incubated for 45 mins by Kinobead based pull down assay	kd	0.5233	uM
Gilteritinib	1424899: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	5.5110	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects localization, decreases expression, affects cotreatment	4
Valproic Acid	decreases methylation, affects cotreatment, decreases expression, affects expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Arsenic Trioxide	increases expression, affects cotreatment	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Hydrogen Peroxide	affects expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	decreases expression, affects binding	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991612	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D2HT	Abcam Raji ACTR3 KO	Cancer cell line	Male
CVCL_UQ04	Abcam Jurkat ACTR3 KO	Cancer cell line	Male
CVCL_WQ88	Abcam K-562 ACTR3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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