Affinage

ARPC1A

Actin-related protein 2/3 complex subunit 1A · UniProt Q92747

Length
370 aa
Mass
41.6 kDa
Annotated
2026-06-09
33 papers in source corpus 14 papers cited in narrative 14 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

ARPC1A (p40/Arc40/SOP2Hs) is an essential subunit of the Arp2/3 complex that drives branched actin nucleation at sites of membrane protrusion, localizing to lamellipodia upon growth-factor stimulation (PMID:9359840). Genetic and biochemical dissection of the yeast ortholog established it as required for Arp2/3 complex integrity, cell viability, and cortical actin patch assembly (PMID:10377407), and resolved three distinct functional surfaces of the subunit: an extended structural arm that directly binds the VCA domain of WASp-family activators to drive nucleation (Kd ~0.45 µM), an interface with p19/ARPC4 needed to propagate WASp-induced activation, and an interface with p15/ARPC5 that suppresses spontaneous nucleation (PMID:15485833, PMID:20071330). ARPC1A is not functionally interchangeable with its paralog ARPC1B: in ARPC1B-deficient immune cells, compensatory ARPC1A upregulation cannot restore WASP-stimulated branched-actin nucleation, leading to loss of podosomes and lamellipodia, weakened cortical F-actin, and downstream B-cell receptor signaling defects (PMID:28368018, PMID:34673575). ARPC1A- and ARPC1B-containing iso-complexes also differ pharmacologically, with CK-666 inhibiting branching only in ARPC1A complexes (PMID:39009834). Through its control of actin-based motility, ARPC1A regulates cell migration and invasion: its loss reduces migration and invasion in cancer cells (PMID:19145645), it is transcriptionally driven by STAT3 and suppresses ferroptosis (PMID:35871131), and it acts as a context-dependent negative regulator of cortical branched actin and migration persistence within the Rac1-WAVE-Arp2/3 pathway (PMID:38059420).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1997 Medium

    Established that ARPC1A is a bona fide subunit of the mammalian Arp2/3 complex acting at the actin cytoskeleton, answering whether the human protein participates in protrusive structures.

    Evidence Peptide sequencing, cDNA cloning, and stimulus-dependent immunofluorescence localization in neutrophils and fibroblasts

    PMID:9359840

    Open questions at the time
    • Did not define molecular role within the complex
    • No nucleation or binding mechanism established
  2. 1999 High

    Demonstrated that the ARPC1A ortholog is essential for complex integrity and cortical actin assembly, establishing it as a structurally indispensable subunit rather than an accessory factor.

    Evidence Immunoprecipitation, gel filtration, gene disruption, and actin patch microscopy in yeast

    PMID:10377407

    Open questions at the time
    • Did not identify which molecular contacts mediate essentiality
    • Activator interaction not addressed
  3. 2004 High

    Identified ARPC1A/Arc40 as a direct VCA-domain contact site, answering how WASp-family activators physically engage the complex through this subunit.

    Evidence Recombinant binding assays with Kd measurement, VCA pulldown, in vitro nucleation, and yeast deletion phenotyping

    PMID:15485833

    Open questions at the time
    • Did not separate VCA contact from other subunit interfaces
    • Human/paralog specificity not addressed
  4. 2010 High

    Resolved three mechanistically distinct functional surfaces of the subunit, explaining how a single subunit both activates WASp-driven nucleation and suppresses leaky nucleation.

    Evidence Systematic analysis of 39 integrated alleles with purification of mutant complexes and in vitro nucleation/VCA binding assays in yeast

    PMID:20071330

    Open questions at the time
    • Defined in yeast; human iso-complex differences not addressed
    • Structural basis at atomic resolution not provided
  5. 2009 Medium

    Linked ARPC1A function to cell motility and identified additional binding context, addressing the cellular consequence of the subunit downstream of actin polymerization.

    Evidence RNAi knockdown with migration/invasion/proliferation assays in pancreatic cancer cells (PMID 19145645) and immunoaffinity-MS identifying Hsp27 interaction (PMID 19579057)

    PMID:19145645 PMID:19579057

    Open questions at the time
    • Hsp27 interaction lacks reciprocal validation and functional follow-up
    • Direct vs indirect motility role not separated
  6. 2017 High

    Showed ARPC1A and ARPC1B are not functionally interchangeable, answering whether the paralogs are redundant within the complex in blood cells.

    Evidence Patient-derived platelet analysis, immunoblot, spreading assays, and megakaryocytic cell knockout across independent patients

    PMID:28368018

    Open questions at the time
    • Molecular basis of non-interchangeability not resolved
    • Did not define downstream signaling consequences
  7. 2021 High

    Defined the signaling consequences of ARPC1A iso-complex deficiency, establishing how isoform-specific nucleation failure propagates to receptor signaling.

    Evidence Patient B-cell F-actin imaging, BCR diffusion, calcium imaging, and phospho-signaling readouts

    PMID:34673575

    Open questions at the time
    • Structural reason ARPC1A complexes resist WASP stimulation not resolved
    • Findings within immunodeficiency context
  8. 2022 Medium

    Placed ARPC1A under STAT3 transcriptional control and linked it to ferroptosis suppression, extending its role beyond direct actin mechanics.

    Evidence Co-IP, ChIP, luciferase reporter, RNAi knockdown with ferroptosis assays, and in vivo tumor model in prostate cancer

    PMID:35871131

    Open questions at the time
    • Mechanistic link between actin function and ferroptosis not defined
    • Single lab
  9. 2024 Medium

    Demonstrated isoform-specific pharmacology and context-dependent regulatory roles, refining how ARPC1A-containing complexes can be distinguished functionally and modulated.

    Evidence Reconstituted iso-complexes with CK-666/CK-869 branching assays (PMID 39009834), triple-inactivation epistasis and rescue in MCF10A/zebrafish (PMID 38059420), and m6A-EML4-ARPC1A co-IP/metastasis study (PMID 38922581)

    PMID:38059420 PMID:38922581 PMID:39009834

    Open questions at the time
    • EML4 interaction lacks reciprocal validation beyond co-IP
    • Mechanism reconciling positive (migration) and negative (cortical branched actin) regulatory roles unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for why ARPC1A-containing iso-complexes differ from ARPC1B-containing complexes in WASP responsiveness and inhibitor sensitivity remains undefined.
  • No atomic-resolution comparison of human ARPC1A vs ARPC1B iso-complexes
  • How transcriptional, signaling, and structural roles integrate in vivo is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 2
Partners
ARPC4ARPC5EML4HSPB1STAT3WASP
Complex memberships
Arp2/3 complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ARPC1A (SOP2Hs) is a component of the mammalian Arp2/3 complex in human neutrophils, and the complex localizes to lamellipodia upon stimulation with serum or PDGF, implicating it in actin cytoskeleton organization at sites of protrusion. Peptide sequencing, cDNA cloning, subcellular localization by immunofluorescence in fibroblasts The Biochemical journal Medium 9359840
1999 Arc40p (yeast ARPC1A ortholog) is an essential component of the yeast Arp2/3 complex; immunoprecipitation confirmed its association, and deletion showed it is required for cell viability, cortical actin patch assembly, and complex integrity (Arc15p is required for association of Arp2p and Arc40p with the complex). Immunoprecipitation, gel-filtration, gene disruption, actin patch microscopy Proceedings of the National Academy of Sciences of the United States of America High 10377407
2001 ARC40 (yeast ARPC1A ortholog) has synthetic genetic interactions with cytoskeletal organization genes (BNI1, ARP2, BIM1), placing it in the cortical actin assembly pathway. Synthetic genetic array (SGA) analysis — systematic double-mutant construction in yeast Science (New York, N.Y.) Low 11743205
2004 ARPC1/Arc40 binds the VCA domain of WASp family activators (Kd ~0.45 µM for recombinant Arc40, close to 0.30 µM for full complex); loss of Arc40 in Δarc40 yeast severely reduces Arp2/3 complex binding affinity for VCA and nucleation activity, and causes loss of actin patches with accumulation of actin cables, demonstrating that Arc40 is an essential VCA contact site. Recombinant protein binding assay, VCA-pulldown, in vitro actin nucleation assay, yeast genetic deletion, actin patch microscopy The Journal of biological chemistry High 15485833
2009 ARPC1A is identified as a direct binding partner of Hsp27 by immunoaffinity purification/mass spectrometry; thiolutin treatment disrupts this interaction and induces peripheral co-localization of phospho-Hsp27 and Arp2/3, linking ARPC1A–Hsp27 interaction to cytoskeletal regulation in endothelial cell adhesion. Immunoaffinity purification, mass spectrometry, immunofluorescence localization Cell stress & chaperones Medium 19579057
2009 ARPC1A silencing by RNAi in AsPC-1 pancreatic cancer cells (which harbor 7q21-q22 amplification) causes a massive reduction in cell migration and invasion, with only a slight decrease in proliferation, establishing ARPC1A as a regulator of cell motility downstream of actin polymerization. RNAi knockdown, cell migration assay, invasion assay, cell proliferation assay, FISH copy-number analysis, qRT-PCR Genes, chromosomes & cancer Medium 19145645
2010 Structure-function analysis of yeast p40/ARPC1 identified three distinct functional surfaces: (1) contact with p19/ARPC4 required for WASp-induced nucleation; (2) contact with p15/ARPC5 that suppresses spontaneous (leaky) nucleation; (3) an extended structural arm that directly binds the VCA domain of WASp and is required for actin nucleation. Lethal alleles at each site produced distinct biochemical defects in purified Arp2/3 complexes. Systematic in vivo allele analysis (39 integrated alleles), purification of mutant Arp2/3 complexes, in vitro actin nucleation assay, VCA binding assay The Journal of biological chemistry High 20071330
2017 Loss of ARPC1B leads to compensatory upregulation of ARPC1A in patient platelets, but ARPC1B-deficient cells cannot support WASP-mediated ARP2/3 nucleation despite elevated ARPC1A, indicating that ARPC1A and ARPC1B are not functionally interchangeable within the ARP2/3 complex in blood cells. Patient-derived platelet lysate analysis, immunoblot, functional platelet spreading assays, megakaryocytic cell knockout Nature communications High 28368018
2021 Despite upregulation of ARPC1A in ARPC1B-deficient cells, ARP2/3 complexes containing ARPC1A cannot be stimulated by WASP to nucleate branched actin; this isoform-specific deficiency leads to loss of WASP-dependent structures (podosomes, lamellipodia) and weakening of cortical F-actin, resulting in increased BCR diffusion, elevated tonic lipid signaling, oscillatory calcium release, and phospho-Akt in B cells. Patient B cell analysis, immunoblot, F-actin imaging, BCR diffusion assay, calcium imaging, phospho-signaling readout JCI insight High 34673575
2022 STAT3 transcriptionally regulates ARPC1A expression in prostate cancer cells; ARPC1A knockdown promotes ferroptosis and reduces cell viability and invasion, as established by Co-IP, ChIP, and luciferase reporter assays confirming STAT3 binding to the ARPC1A promoter. Co-IP, ChIP, luciferase reporter assay, RNAi knockdown, ferroptosis assay, in vivo tumor model Human cell Medium 35871131
2024 ARPC1A-containing ARP2/3 iso-complexes are inhibited by both CK-666 and CK-869 for actin branching, whereas ARPC1B-containing complexes are only inhibited by CK-869; both inhibitors block linear actin filament formation in ARPC1A- and ARPC1B-containing complexes when activated by SPIN90. This demonstrates isoform-specific pharmacology of ARP2/3 complexes. Reconstituted recombinant Arp2/3 iso-complexes with defined subunit composition, in vitro actin polymerization/branching assays with pharmacological inhibitors, macrophage phagocytosis and migration assays EMBO reports High 39009834
2024 ARPC1A inactivation (KD or KO) combined with inactivation of arpin and CYFIP2 synergistically enhances cortical branched actin polymerization and migration persistence in human MCF10A cells and zebrafish endodermal cells, identifying ARPC1A as a negative regulator of cortical branched actin in the Rac1-WAVE-Arp2/3 migration pathway. siRNA knockdown, CRISPR knockout, live cell migration assay, zebrafish in vivo migration, vimentin re-expression rescue experiment Journal of cell science Medium 38059420
2024 EML4 interacts with ARPC1A to modulate cytoskeletal dynamics and enhance lamellipodia formation, cellular motility, local invasion, and metastasis in lung adenocarcinoma; m6A hypermethylation of EML4 mRNA promotes its translation leading to ARPC1A interaction. m6A epitranscriptomic profiling, co-immunoprecipitation (EML4–ARPC1A interaction), functional migration/invasion assays, in vivo metastasis model Cancer discovery Medium 38922581
2016 ARPC1A was identified as a component of the PKD2 interaction network; chemical cross-linking/mass spectrometry detected ARPC1A (along with the full Arp2/3 complex) as a PKD2-interacting protein in cytosolic and Golgi-enriched fractions, suggesting a direct protein–protein interaction. Affinity enrichment, chemical cross-linking, mass spectrometry Journal of proteome research Low 27559607

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science (New York, N.Y.) 1642 11743205
2010 Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. Human molecular genetics 299 20570966
1997 Mammalian actin-related protein 2/3 complex localizes to regions of lamellipodial protrusion and is composed of evolutionarily conserved proteins. The Biochemical journal 186 9359840
1999 Genetic dissection of the budding yeast Arp2/3 complex: a comparison of the in vivo and structural roles of individual subunits. Proceedings of the National Academy of Sciences of the United States of America 170 10377407
2017 Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease. Nature communications 163 28368018
2011 Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms. PLoS genetics 89 21533175
2017 Genome-wide identification of genes essential for podocyte cytoskeletons based on single-cell RNA sequencing. Kidney international 69 28709640
2004 ARPC1/Arc40 mediates the interaction of the actin-related protein 2 and 3 complex with Wiskott-Aldrich syndrome protein family activators. The Journal of biological chemistry 45 15485833
2009 Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton. Cell stress & chaperones 43 19579057
2013 CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity. Oncogene 42 23644663
2009 Characterization of the 7q21-q22 amplicon identifies ARPC1A, a subunit of the Arp2/3 complex, as a regulator of cell migration and invasion in pancreatic cancer. Genes, chromosomes & cancer 41 19145645
2018 Silver nanoparticles impair zebrafish skeletal and cardiac myofibrillogenesis and sarcomere formation. Aquatic toxicology (Amsterdam, Netherlands) 28 29729476
2021 ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells. JCI insight 25 34673575
2010 The p40/ARPC1 subunit of Arp2/3 complex performs multiple essential roles in WASp-regulated actin nucleation. The Journal of biological chemistry 24 20071330
2022 Differential expression and analysis of extrachromosomal circular DNAs as serum biomarkers in lung adenocarcinoma. Journal of clinical laboratory analysis 22 35441736
2020 Development and validation of hub genes for lymph node metastasis in patients with prostate cancer. Journal of cellular and molecular medicine 21 32130760
2024 The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma. Cancer discovery 19 38922581
2022 A Bioinformatics Perspective on the Dysregulation of Ferroptosis and Ferroptosis-related Immune Cell Infiltration in Alzheimer's Disease. International journal of medical sciences 19 36438927
2024 CK-666 and CK-869 differentially inhibit Arp2/3 iso-complexes. EMBO reports 15 39009834
2022 ARPC1A is regulated by STAT3 to inhibit ferroptosis and promote prostate cancer progression. Human cell 12 35871131
2019 Cardiomyopathy and altered integrin-actin signaling in Fhl1 mutant female mice. Human molecular genetics 12 30260394
2016 Protein Interaction Network of Human Protein Kinase D2 Revealed by Chemical Cross-Linking/Mass Spectrometry. Journal of proteome research 11 27559607
2018 Differential expression of serum proteins in multiple myeloma. Experimental and therapeutic medicine 9 30651846
2023 Microcystin-LR exposure interfered maintenance of colonic microenvironmental homeostasis in rat. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 7 36657700
2019 Screening of Candida albicans GRACE library revealed a unique pattern of biofilm formation under repression of the essential gene ILS1. Scientific reports 7 31235750
2025 Pan-cancer analysis of Arp2/3 complex subunits: focusing on ARPC1A's role and validating the ARPC1A/c-Myc axis in non-small cell lung cancer. Frontiers in immunology 4 39867911
2024 Inactivating negative regulators of cortical branched actin enhances persistence of single cell migration. Journal of cell science 4 38059420
2025 Multi-omics analysis provides new insights into the molecular mechanisms underlying colostral immunoglobulin G absorption in the gut of neonatal goat kids. Animal nutrition (Zhongguo xu mu shou yi xue hui) 3 40487106
2013 Testing the utility of an integrated analysis of copy number and transcriptomics datasets for inferring gene regulatory relationships. PloS one 3 23737949
2025 Screening and identification of protein 29 of Echinococcus granulosus interacting molecules. Frontiers in cellular and infection microbiology 0 40384981
2025 Multi-omics whole-genome characterization of the copy number landscape of metastatic pancreatic ductal adenocarcinoma. iScience 0 40792032
2025 Hyperlipidemia-associated specific modules and hub genes revealed by integrative methods of WGCNA and MetaDE. Frontiers in genetics 0 41446394
2024 Experimental Validation and Multi-omics Analysis Identified ARPC1A as a Novel Oncogene and Potential Therapeutic Target in Glioblastoma. Journal of Cancer 0 38911374

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