Affinage

ACTR3

Actin-related protein 3 · UniProt P61158

Length
418 aa
Mass
47.4 kDa
Annotated
2026-06-09
39 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACTR3 (ARP3) is a core subunit of the Arp2/3 complex that nucleates branched actin filament networks underlying cell-edge protrusion and motility (PMID:33598464). Conditional loss of Actr3 abolishes functional Arp2/3 expression, eliminates lamellipodia and membrane ruffling, slows peripheral actin turnover, and degrades directional and collective migration; cells compensate by upregulating FMNL2/3 formins and switching to filopodia-based protrusion, revealing antagonistic balance between Arp2/3- and formin-based actin networks (PMID:33598464). This branched-actin function is co-opted in several cellular contexts: ACTR3 is required for Salmonella phagocytosis in macrophages (PMID:31594818), and the Arp2/3 complex partners with CORO1C to assemble branched actin needed for p62/SQSTM1 body formation and autophagosome integrity during macroautophagy (PMID:41968673). In cancer, ACTR3 promotes migration, invasion, and epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma (PMID:34790395), physically associates with nuclear BRAFV600E in thyroid cancer where it correlates with aggressive disease and vemurafenib resistance (PMID:35968344), and is engaged by PKD2 at the Golgi and in the cytosol (PMID:27559607). ACTR3 activity is tuned post-translationally: lysine 2-hydroxyisobutyrylation at K42, controlled by SIRT1 and HDAC1, is reduced in psoriatic skin, and loss of this modification activates the TAK1-MK2-HSP27 pathway to drive keratinocyte hyperproliferation (PMID:42089462).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2016 Medium

    Whether ACTR3, as part of the intact Arp2/3 complex, engages specific upstream regulators at defined organelles was unresolved; this work placed the complex in direct contact with a signaling kinase at the Golgi.

    Evidence Affinity enrichment with chemical cross-linking/mass spectrometry and subcellular fractionation showing PKD2 binding to the seven-subunit Arp2/3 complex including ACTR3

    PMID:27559607

    Open questions at the time
    • Functional consequence of the PKD2-Arp2/3 interaction not established
    • Whether ACTR3 is a direct contact point versus a complex-level interaction unresolved
  2. 2019 Medium

    It was unclear which actin machinery components are essential for bacterial internalization in macrophages; an unbiased screen placed ACTR3 in the actin dynamics pathway required for phagocytosis.

    Evidence Genome-wide CRISPR knockout screen in THP-1 macrophages with validation that ACTR3 loss confers Salmonella uptake resistance

    PMID:31594818

    Open questions at the time
    • Mechanistic step of phagocytic actin remodeling that requires ACTR3 not dissected
    • Upstream nucleation-promoting factors not identified
  3. 2021 High

    The cell-biological consequences of removing ACTR3 had not been cleanly defined genetically; conditional knockout established its non-redundant role in lamellipodial actin and revealed compensatory formin upregulation.

    Evidence Tamoxifen-inducible Actr3 knockout mouse fibroblasts with immunofluorescence, FRAP, and live-cell migration/chemotaxis assays

    PMID:33598464

    Open questions at the time
    • Molecular trigger for FMNL2/3 induction upon Arp2/3 loss not defined
    • Phenotypes characterized in fibroblasts; cell-type generality not tested
  4. 2021 Medium

    Whether ACTR3 contributes to cancer cell aggressiveness was open; knockdown in PDAC linked it to invasion and EMT.

    Evidence siRNA knockdown in PDAC cell lines with transwell invasion assays, EMT marker Western blots, and F-actin staining

    PMID:34790395

    Open questions at the time
    • Whether EMT changes are a direct consequence of actin nucleation or downstream signaling unresolved
    • In vivo validation absent
  5. 2021 Low

    Upstream regulators of ACTR3 abundance were poorly mapped; LUZP1 loss and miR-486-5p were reported to alter ACTR3 levels.

    Evidence CRISPR Luzp1 knockout in fibroblasts with Western blotting for ACTR3 and phospho-cofilin; separately, miR-486-5p transfection and exosomal tracking in gastric cancer-associated mesothelial cells

    PMID:33869174 PMID:34686196

    Open questions at the time
    • ACTR3 changes are indirect readouts with no direct functional manipulation of ACTR3
    • Direct versus indirect regulation not distinguished
  6. 2022 Medium

    A non-cytoskeletal, nuclear association for ACTR3 was unknown; proteomics identified it as the top nuclear BRAFV600E partner in thyroid cancer with links to aggressiveness and drug resistance.

    Evidence Nuclear/cytosolic fractionation, proteomic analysis of BRAFV600E immunoprecipitates, functional assays, xenografts, and IHC on 100 PTC specimens

    PMID:35968344

    Open questions at the time
    • Mechanism by which nuclear ACTR3-BRAFV600E drives resistance unresolved
    • Whether the canonical Arp2/3 complex is involved in the nucleus not addressed
  7. 2026 Medium

    How ACTR3 activity is tuned post-translationally and links to inflammatory disease was unknown; a site-specific Khib modification at K42 was shown to gate keratinocyte proliferation via a defined kinase pathway.

    Evidence Khib profiling by mass spectrometry of human skin, K42A mutation in an IMQ-induced psoriatic mouse model, SIRT1/HDAC1 manipulation, and TAK1 antagonist rescue

    PMID:42089462

    Open questions at the time
    • How K42-Khib alters actin nucleation biochemically not resolved
    • Link between K42 modification status and TAK1-MK2-HSP27 activation mechanistically incomplete
  8. 2026 Medium

    Whether branched actin contributes to autophagosome biogenesis was unclear; CORO1C was shown to bridge the ARP2-ARP3 complex to branched actin assembly required for p62 body formation and autophagosome integrity.

    Evidence Genome-wide screen in mouse haploid ESCs, CORO1C-ACTR2/ACTR3 interaction studies, and coro1c-/- mouse autophagy phenotyping by TEM and immunofluorescence

    PMID:41968673

    Open questions at the time
    • ACTR3's specific role inferred from CORO1C-Arp2/3 interaction rather than direct ACTR3 manipulation
    • Site of branched actin assembly relative to the autophagosome not pinpointed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ACTR3's single actin-nucleation activity is differentially deployed and regulated across migration, phagocytosis, autophagy, nuclear signaling, and disease contexts remains unresolved.
  • No structural model linking K42-Khib to nucleation activity
  • Context-specific nucleation-promoting factors not systematically mapped
  • Non-canonical nuclear function not mechanistically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005634 nucleus 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
GO:0005856 cytoskeleton 1 R-HSA-9612973 Autophagy 1
Partners
ACTR2BRAFCORO1CLUZP1PKD2
Complex memberships
Arp2/3 complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Conditional knockout of murine Actr3 (encoding Arp3) causes near-complete loss of functional Arp2/3 complex expression, abolished lamellipodia formation and membrane ruffling, reduced actin turnover rates at the cell periphery, compromised directionality of migration and collective migration, and paradoxically enhanced cell spreading via induction of filopodia. Induced Arp3 depletion also reproducibly increased FMNL2/3 formin expression, correlating with explosive filopodia induction, revealing a compensatory relationship between Arp2/3 and formin-based actin networks. Conditional (tamoxifen-inducible) Actr3 knockout mouse fibroblast cell lines; immunofluorescence; FRAP; live-cell migration assays; chemotaxis assays Frontiers in cell and developmental biology High 33598464
2022 Nuclear BRAFV600E physically interacts with Arp2/3 complex members ACTR2 (ARP2) and ACTR3 (ARP3) in thyroid cancer cells; proteomic analysis identified ACTR3 as the most enriched nuclear BRAFV600E partner. ACTR3 expression was correlated with lymph node stage and extrathyroidal extension, and was validated with functional assays demonstrating a role in aggressive behavior and vemurafenib resistance. Nuclear/cytosolic fractionation; proteomic analysis of BRAFV600E immunoprecipitates; functional assays in PTC cells and xenograft mouse model; IHC on 100 PTC specimens American journal of cancer research Medium 35968344
2016 PKD2 (protein kinase D2) physically interacts with the entire seven-subunit Arp2/3 complex, including ACTR3, in both cytosolic and Golgi-enriched subcellular fractions, as demonstrated by affinity enrichment combined with chemical cross-linking/mass spectrometry, providing evidence of a direct PKD2–Arp2/3 protein-protein interaction. Affinity enrichment; chemical cross-linking/mass spectrometry (XL-MS); subcellular fractionation into cytosolic and Golgi fractions Journal of proteome research Medium 27559607
2021 Knockdown of ACTR3 in pancreatic ductal adenocarcinoma (PDAC) cells significantly inhibited invasive and migratory capacity, altered F-actin distribution, and changed the expression of EMT markers (e.g., E-cadherin, vimentin), indicating that ACTR3 promotes cell migration and invasion by inducing epithelial-mesenchymal transition in PDAC. siRNA knockdown of ACTR3 in PDAC cell lines; transwell migration/invasion assays; Western blotting for EMT markers; phalloidin staining of F-actin Journal of gastrointestinal oncology Medium 34790395
2021 LUZP1 loss in mouse fibroblasts (CRISPR/Cas9 knockout) induces changes in ACTR3 (ARP3) protein levels and phospho-cofilin ratios, suggesting that LUZP1 regulates actin polymerization through the Arp2/3 pathway beyond its role in filament bundling. CRISPR/Cas9 Luzp1 knockout in mouse fibroblasts; Western blotting for ACTR3 and phospho-cofilin; cell migration and invasion assays Frontiers in cell and developmental biology Low 33869174
2026 Lysine 2-hydroxyisobutyrylation (Khib) at the K42 site of ACTR3 is reduced in psoriatic lesional skin. Decreased K42-Khib modification (modeled by K42A mutation) exacerbates psoriatic inflammation and keratinocyte proliferation. The deacetylases SIRT1 and HDAC1 reduce ACTR3 Khib modification levels. Reduced K42-Khib of ACTR3 promotes keratinocyte proliferation by activating the TAK1-MK2-HSP27 signaling pathway; TAK1 antagonists reversed this effect. Khib-modified protein profiling by mass spectrometry on human psoriatic and healthy skin biopsies; ACTR3 K42A mutation experiments in IMQ-induced psoriatic mouse model; Western blotting; TAK1 antagonist treatment; SIRT1/HDAC1 knockdown/overexpression experiments The FEBS journal Medium 42089462
2019 ACTR3 was identified as a host factor required for Salmonella uptake in human macrophages; CRISPR knockout of ACTR3 in THP-1 macrophages conferred resistance to Salmonella infection, placing ACTR3 in the actin dynamics pathway necessary for bacterial phagocytosis. Genome-wide CRISPR knockout screen in THP-1 macrophages; validation of individual gene knockouts for Salmonella uptake resistance mBio Medium 31594818
2026 CORO1C interacts with the ACTR2/ARP2-ACTR3/ARP3 complex; this interaction is essential for branched actin network assembly, SQSTM1/p62 body formation, and maintaining autophagosome structural integrity during macroautophagy. Genome-wide loss-of-function screen in mouse haploid ESCs; CORO1C-ACTR2/ACTR3 interaction studies; coro1c-/- mouse model with autophagy phenotype analysis by TEM and immunofluorescence Autophagy Medium 41968673
2021 miR-486-5p downregulates ACTR3 expression (along with SMAD2 and CDK4) in gastric cancer-associated peritoneal mesothelial cells (HMrSV5); decreased exosomal delivery of miR-486-5p from peritoneal metastasis gastric cancer cells leads to increased ACTR3 expression and promotes EMT progression in recipient cells. miRNA array; qRT-PCR; Western blotting for ACTR3, SMAD2, CDK4; miR-486-5p transfection; laser confocal microscopy for exosomal delivery tracking World journal of surgical oncology Low 34686196

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Zinc-finger protein 331, a novel putative tumor suppressor, suppresses growth and invasiveness of gastric cancer. Oncogene 73 22370639
2019 A Genome-Wide Knockout Screen in Human Macrophages Identified Host Factors Modulating Salmonella Infection. mBio 45 31594818
2021 Induced Arp2/3 Complex Depletion Increases FMNL2/3 Formin Expression and Filopodia Formation. Frontiers in cell and developmental biology 37 33598464
2019 Transcriptome analysis reveals microvascular endothelial cell-dependent pericyte differentiation. Scientific reports 32 31666598
2018 A genome-wide scan for signatures of selection in Azeri and Khuzestani buffalo breeds. BMC genomics 32 29890939
2019 Discovering novel lung cancer associated antigens and the utilization of their autoantibodies in detection of lung cancer. Immunobiology 24 31839396
2023 Extracellular vesicles from human Fallopian tubal fluid benefit embryo development in vitro. Human reproduction open 21 36895886
2016 Mapping epigenetic changes to the host cell genome induced by Burkholderia pseudomallei reveals pathogen-specific and pathogen-generic signatures of infection. Scientific reports 19 27484700
2012 Differences in the proteome of high-grade versus low-grade canine cutaneous mast cell tumours. Veterinary journal (London, England : 1997) 18 22578690
2021 Decreased exosome-delivered miR-486-5p is responsible for the peritoneal metastasis of gastric cancer cells by promoting EMT progress. World journal of surgical oncology 17 34686196
2020 Identification of mRNAs and lncRNAs Involved in the Regulation of Follicle Development in Goat. Frontiers in genetics 15 33391342
2021 LUZP1 Controls Cell Division, Migration and Invasion Through Regulation of the Actin Cytoskeleton. Frontiers in cell and developmental biology 14 33869174
2021 ACTR3 promotes cell migration and invasion by inducing epithelial mesenchymal transition in pancreatic ductal adenocarcinoma. Journal of gastrointestinal oncology 12 34790395
2016 Protein Interaction Network of Human Protein Kinase D2 Revealed by Chemical Cross-Linking/Mass Spectrometry. Journal of proteome research 11 27559607
2024 PLD1 promotes spindle assembly and migration through regulating autophagy in mouse oocyte meiosis. Autophagy 10 38513669
2023 Methylation Levels in the Promoter Region of FHIT and PIAS1 Genes Associated with Mastitis Resistance in Xinjiang Brown Cattle. Genes 10 37372369
2018 SOX2OT knockdown derived changes in mitotic regulatory gene network of cancer cells. Cancer cell international 10 30202240
2016 Acute Hypoxic Stress Affects Migration Machinery of Tissue O2-Adapted Adipose Stromal Cells. Stem cells international 10 28115943
2024 Minimal Change Disease: Pathogenetic Insights from Glomerular Proteomics. International journal of molecular sciences 9 38891801
2020 HBV DNA integrates into upregulated ZBTB20 in patients with hepatocellular carcinoma. Molecular medicine reports 9 32319639
2023 Modified Danzhi Xiaoyao Powder (MDXP) improves the corneal damage in dry eye disease (DED) mice through phagocytosis. Journal of ethnopharmacology 8 38070838
2020 Identification of hub genes and pathways in cholangiocarcinoma by coexpression analysis. Cancer biomarkers : section A of Disease markers 8 32116234
2021 BSG/CD147 and ACE2 receptors facilitate SARS-CoV-2 infection of human iPS cell-derived kidney podocytes. bioRxiv : the preprint server for biology 7 34816259
2022 Genome-wide DNA methylation profiles of autism spectrum disorder. Psychiatric genetics 6 35353793
2019 Plasma Membrane Proteomic Profile Discovers Macrophage-capping Protein Related to Latent HIV-1. Current HIV research 5 31057110
2024 BAG3 regulates cilia homeostasis of glioblastoma via its WW domain. BioFactors (Oxford, England) 4 38655699
2025 Dendrobium huoshanense polysaccharide inhibits NSCLC proliferation and immune evasion via FXR1-IL-35 axis signaling pathway. Journal of natural medicines 3 40259042
2024 Risk prediction model construction for asthma after allergic rhinitis by blood immune T effector cells. Medicine 2 38394538
2019 Fine-mapping scan of bipolar disorder susceptibility loci in Latino pedigrees. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2 30779416
2026 Single-cell RNA sequencing reveals the therapeutic mechanism of Calvatia lilacina in promoting wound healing of anal fistula. Chinese medicine 1 41495793
2023 Genome-wide association analysis of neck ring traits in NongHua ma male ducks. British poultry science 1 37610317
2022 Nuclear interaction of Arp2/3 complex and BRAFV600E promotes aggressive behavior and vemurafenib resistance of thyroid cancer. American journal of cancer research 1 35968344
2026 A plasma proteomic signature of the actin-coagulation axis accurately predicts progression to active tuberculosis. Frontiers in microbiology 0 41669692
2026 Identification of discriminative plasma protein biomarkers for recent Mycobacterium tuberculosis infection: a pilot data‑independent acquisition mass spectrometry‑based proteomics study. BMC infectious diseases 0 41922977
2026 CORO1C (coronin 1C) promotes autophagosome formation by coordinating branched actin network dynamics. Autophagy 0 41968673
2026 Genetic determinants of fatigue up to 2 years after radiotherapy in prostate cancer patients. Nature communications 0 42020408
2026 ACTR3 enhances the hyperproliferation of psoriatic keratinocytes by activating the TAK1-MK2-HSP27 pathway. The FEBS journal 0 42089462
2024 Should it stay or should it go: gap junction protein GJA1/Cx43 conveys damaged lysosomes to the cell periphery to potentiate exocytosis. Autophagy 0 39394955
2022 Dietary Inclusion of Dried Chicory Root Affects Cecal Mucosa Proteome of Nursery Pigs. Animals : an open access journal from MDPI 0 35804609

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